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PHC 122 Lecture

Biopharmaceutics and Pharmacokinetics

DRUG
 Synthetic
 Semi-synthetic
 Natural
 Biological

Definition of Terms:
1. Biopharmaceutics
 deals with the physical and chemical properties of the 7. Biophase
drugs and their proper dosage as related to the onset,  is the actual site of actions of drugs in the body. Biophase
duration, and intensity of the drug action. may be the surface of the cell or within the cell, one of the
organelles.
2. Pharmacokinetics
 Science of the kinetics of drug absorption, distribution, and 8. Bioavailability
elimination (excretion and metabolism). Mathematical  is defined as the relative amount of drug from an
application of ADME system administered dosage form which enters the systemic
circulation and the rate at which the drug appears in the
3. Clinical Pharmacokinetics blood stream
 application of Pharmacokinetic methods to drug therapy.
9. Bioequivalence
4. Pharmacodynamics  the relationship between two preparations of the same
 refers to the relationship between the drug concentration drug in the same dosage form that have a similar
at the site of action ( Receptor ) and pharmacologic bioavailability
response, including chemical and physiological effects that
influence the interaction of drug with the receptor.

5. Receptor
 is a site in the biophase to which the drug molecules can
be bound. Eg. Binding of a drug in blood plasma.

10. Drug-receptor - is the combining of a drug molecule with the

receptor for which it has affinity and initiation of pharmacologic
response by its intrinsic activity.

6. Protein bound
 binding of a drug to proteins in blood plasma.
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11. Clearance – is the hypothetical volume (possibility) of

distribution in milliliters of the unmetabolized drug cleared per unit
of time ( ml/min or ml/hr ) by anyway of drug removal ( renal,
hepatic, and other pathways of elimination )

12. Extravascular administration- refers to all routes of

administration except for those in which the drug is introduced
directly into the blood stream. Eg. IM, SC, PO, Oral, Rectal,
Intraperitoneal and Topical.

13. Central Compartment – is the sum of all body regions ( organs

and tissues ) in which the drug concentration equilibrium with that
in blood or plasma. The blood or plasma is always part of the central
compartment.

14. Creatinine clearance- is the ratio of creatinine excreted in urine

to the concentration of creatinine in plasma. The creatinine
clearance decreases with renal impairment and with age.

2. Importance /Application of Biopharmaceutics and

Pharmacokinetics
A. Drug Monitoring
B. Patient care in the clinical field
C. Clinical Research in the area of drug development
D. Critical drug evaluation and approval process in the
regulatory field.
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DIFFERENCE IN DRUG EFFECT

 A company is going to
market a new dosage form
of a certain drug. The dose is
known. When this dosage
form is administered to a
healthy human the drug
may not released quickly. In
this case the action of the
drug will be delayed. In another case if the drug is released
all at a time then the duration of action of the drug will be
very short.
 So with the knowledge of biopharmaceutics we can
change various formulation factors to obtain optimum
onset of action and duration of action.

GENERIC DRUG CONTROVERSY

 A company is marketing tablets of a certain drug. Now it
wants to change a few ingredients or some formulation
factors.
 The new tablets may not behave similarly as the previous
one. So the bioavailability of new tablets are compared
with the old tablets. If it is found that the bioavailability of
the newer tablets are equivalent (i.e bioequivalent) to that
of older tablets then the new tablets will be permitted to
market (by FDA).
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DRUG DELIVERY SYSTEM  A company is marketing the tablets of a certain drug. Now
1. Local and Systemic Drug Administration they have planned to make transdermal dosage form of
2. Common Routes of Drug Administration the same drug. To establish its efficacy the bioavailability
 Intravascular of the transdermal dosage form is compared to that of the
 Extravascular established tablet dosage form.
 If both are found to be closer then the transdermal
1. Local and Systemic Drug Administration dosage form will be accepted by FDA.
 The local route is the simplest mode of administration of a
drug at the site where the desired action is required.
 When the systemic absorption of a drug is desired, III. LADMER System
medications are usually administered by two main routes:
the enteral route and the parenteral route. Liberation, Absorption, Distribution, Metabolism, Elimination, and
Response
 In the relationship between the dose and effectiveness or
dose response, not only the amount of drug administered
and the pharmacological effect of the drug are of
importance but many other factors are responsible for the
entrance of a drug into the body.
 These factors are based on the physical and chemical
properties of the drug substance and of the drug product.

Factors which influence the “Fate of the drugs” or the entire cycle
processes which is describe as the LADMER system.
1. Whether the blood level curve reach its peak rapidly or
slowly depends on the route of administration
2. Dosage form
3. The liberation of the drug from the dosage form
4. Diffusion, Penetration and permeation of the drug
5. Its distribution within the body fluids and tissues
6. Type, amount and rate of biotransformation
7. Recycling process (enterohepatic recycling)
8. Elimination
9. Individual disposition
10. Diseases

The LADMER System is key to the following tasks:

1. Developments of new active compounds, analogs, or
derivatives
2. Development of new dosage forms with desired release
characteristics
3. Determination of pharmacokinetic parameters and
pharmacokinetic drug product profiles
4. Determination and evaluation of bioavailability
5. selection of the most appropriate route of administration
6. Determination of effective dose sizes
7. adjustment of dosage regimen to achieved therapeutic
concentration of drug in the body base physiologic and
pathologic factors.
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The earliest equation to explain the rate of dissolution when the

process is diffusion controlled and involves no chemical reaction was
1. Liberation- Is the first step which determines onset of action, rate
given by Noyes and Whitney:
of absorption, availability which is true for all drugs by all routes of
administration except IV and per oral use of true solutions.
dC/dt = dissolution rate of the drug,
 rate limiting step in LADMER System.
k = dissolution rate constant (first order),
 It is controlled by the characteristics of the drug. Applies
Cs = concentration of drug in the stagnant layer (also called as
to drugs given orally
the saturation or maximum drug solubility), and
 The release of the drug from its dosage form or from the
Cb = concentration of drug in the bulk of the solution at time t.
formulation (Drug Dosage Form)
 Dissolution process takes place after release of drug from
the dosage form.
 Dissolution process is proportional to the ADMER.

Influence of Some Parameters on Dissolution Rate of Drug:

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Danckwert’s Model for drug dissolution

 Danckwert did not approve of the existence of a stagnant
layer and suggested that turbulence in the dissolution
1. Tablet disintegration
medium exists at the solid/liquid interface.
 disintegrants or disintegrating agents which promote
 As a result, the agitated fluid consisting of macroscopic
break-up of the tablets after administration to smaller
mass of eddies or packets reach the solid/liquid interface
particles for ready drug availability.. Eg. Alginic acid,
in a random fashion due to eddy currents, absorb the
microcrystalline cellulose, sodium starch glycolate.
solute by diffusion and carry it to the bulk of the solution.

The diffusion layer model and the Danckwert’s model were based on
2. Inert Ingredient/ Solvent effects
two assumptions:
 an agent to dissolve
1. The rate-determining step that controls dissolution is the
pharmaceutical substance or a drug
mass transport.
in the preparation
2. Solid-solution equilibrium is achieved at the solid/liquid
and inert ingredient
interface.
use to add bulkiness
and stability of the
drug compounds..
Eg. Purified H2O,
Glycerin, sterile water for injection,
water for injection.

3. Solubility
 drug substance administered
by any route possess some
solubility for systemic
absorption and the
therapeutic response.
 Poorly soluble compounds may inhibit incomplete or
erratic absorption

4. Drug pH conc
 is one of the most important involved in the
formulation process. As the pH of the solution is
increased the quantity of drug in solution increases
 Dissolution is a process in which a solid substance because the water-soluble ionization salt is form.
solubilizes in a given solvent i.e. mass transfer from the
solid surface to the liquid phase.
 Rate of dissolution is the amount of drug substance that
goes in solution per unit time under standardized
conditions of liquid/solid interface, temperature and
solvent composition

3. Formulation and Patient factors affecting Liberation Process.

Formulation factors:
1. Tablet disintegration
2. Inert Ingredient/ Solvent effects
3. Solubility
4. Drug pH conc.
5. Salt form
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5. Salt form Membrane - Anatomy

 Most drugs are either weak acids or weak bases. One  Membranes- are boundary surfaces which divide and
of the easiest approaches to enhance the solubility connect.
and dissolution rate of such drugs is to convert them  In biology membranes are barriers between
into their salt forms. morphological and functional units.
 Generally, with weakly acidic drugs, a strong base  Responsible for the uptake of liquid and solid
salt is prepared such as the sodium and potassium materials, for extrusion of endogenous and waste
salts of barbiturates and sulphonamides. materials, for permeation and transport mechanism.
 In case of weakly basic drugs, a strong acid salt is  Membranes are lipid in nature.
prepared like the hydrochloride or sulphate salts of
several alkaloidal drugs.

 If we look at the dissolution profile of various salts.

 Salts of weak acids and weak bases generally have
much higher aqueous solubility than the free acid or
base, therefore if the drug can be given as a salt the Structures and functions of membrane
solubility can be increased and we should have
improved dissolution. One example is Losartan 1. Cell coat
potassium.  composed of chondroitin , H2SO4, hyaluronic acid,
collagen, elastin, sialic acid
Patient factor (Liberation- Absorption process):  Function: principal component of connective tissues ,
1. Absorbing surface ( area ) adsorption of compounds.
2. Blood Flow
3. Disease States
4. Interaction with food, other drugs.
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2. Cell membrane
 composed of proteins, triglycerides , steroids ( cholesterol)
, Phospholipids ( lecithin ) .
 Function: Hydrophilic layer for proteins, lipophilic,
bimolecular( barrier ).

Properties of membrane

1.Permeability- Lipid soluble unionized substances dissolve in the  Low molecular weight substances such as drugs that are
lipid membrane during transfer. delivered to the brain via the circulatory system cannot
 Water soluble, lipid- soluble substance of smaller readily permeate the blood-brain barrier by translocation
molecular weight transfer through water-filled pores in the across intercellular channels between endothelial cells
membrane. rather by diffusion or active transport across the cell
 Substance may combined with a carrier in the membrane membrane.
and transfer to it as drug carrier- active transport and
facilitated transport VI. Drug- Receptor Interactions
 Solid substances and oil droplets may transfer the 1. Structural – non specific drugs
membrane in a vesicle-- pinocytosis 2. Structural – specific drugs
3. Receptors
2. Surface tension- very low due to adsorption of protein to the a. Drug receptor Interactions
outside of the lipid layer. b. Enzyme –linked receptors
c. Channel Linked receptors
3. Electrical properties- membrane potential due to different
distribution of ions in the extracellular and intracellular fluid. 1. Structural non-specific drugs
 pharmacologic action is not
To get across most membranes, the drug must be dependent on the chemical
relatively non polar structure.
To be soluble in water, a drug must be polar  structures affect physicochemical
If a drug is too nonpolar, it may be not be water soluble, or properties.
may bind too tightly to components in food, or to proteins  depends on the thermodynamic
in the blood. activity
 Drugs act exclusively by physical
Types of functional or anatomic membranes and their permeability means outside of cells.
 Neutralization of stomach acid by
antacids is a good example.
 include general anesthetics,
hypnotics together
 with a few bactericidal
compounds and insecticides.

2. Structural – specific drugs

 Pharmacologic actions depends
on the chemical structure of
drugs
 it attaches to 3 dimensional structure of a receptor in the
biophase.
 functional groups, electronic distribution, topographic
mirror images are to all drugs to bind with certain
receptors
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 For example, levo,-phenol has narcotic, analgesic, and  hormone, drug the first messenger, binds to the
antitussive properties, whereas its mirror image, Dextro cell via a receptor.
Phenol , has only antitussive activity.

Insulin binding to its receptor results in autophosphorylation of the

3. Receptors
insulin receptor β-subunits on tyrosine amino acids. Insulin receptor
 are all specific molecules, molecules complexes, or parts
autophosphorylation activates the insulin receptor substrates (IRS-
of these, which bind the drug chemically, the resulting
1/2) and phosphatidylinositol (PI-3) kinases leading to a cascade of
complex exerts a pharmacologic action.
events that ultimately leads to GLUT-4 translocation and glucose
uptake into tissues.

3-a. Drug receptor Interactions

 In biophase may initiate responses by altering permeability
of membranes by interfering with transport mechanism.
 may act on enzymes
Enzyme Linked- receptors:
1. Insulin
2. Epidermal growth factor
3. platelet derived factor

3-b Enzyme –linked Receptors

 may act on enzymes
Enzyme Linked- receptors:
1. Insulin
2. Epidermal growth factor
3. platelet derived factor signals from a group of
endogenous compounds.
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4-c. Channel Linked receptors

 more complicated in their structure than enzyme – linked
receptors.
 Receptor: nicotinic receptors, 5HT, NMDA, GABA

2. Partial agonist- Drugs that are only partly as effective as agonist

no matter the dose employed.
Eg. Buprenorphine®, Naloxone® and ® are partial agonists.

3. Antagonist – Drugs that bind

to receptors without regulatory
but their binding blocks the
binding of the endogenous
agonist.
Eg. Ca Channel Blockers, Beta
Blockers, Angiotensin II
Antagonists
Ca Channel Blocker: nifedipine, diltiazem, verapamil

Effects of Drugs on Receptors:

1. Agonist
2. Partial Agonist
3. Antagonist
4. Competitive Antagonist
5. Non- competitive Antagonist

1. Agonist Drugs –Drugs that bind to physiological receptors and

mimic the regulatory effects of endogenous signaling compounds.
Eg: dopamine, apomorphine, and nicotine.
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4. Competitive Antagonist
 Drug is displace from drug-receptor binding by another
chemical ( antagonist ).
 reversible
 depends on actual drug and antagonist concentration in
the biophase ( law of mass action ).

Linkage Receptors Agonist Antagonist

Stimulation Beta fenoterol Propranolol
H2 Histamine Cimetidine
Inhibition Alpha 2 Clonidine Yohimbine
Dopamine Levodopa Haloperidol
Opioid Morphine Naloxone

Example of drugs whose action is modulated by Adenylate Cyclase-

Linked Receptors

Drug Receptor Theories

1. Hypothesis of Clark
2. Hypothesis of Ariens and Stepheson
5. Non- Competitive Antagonist 3. Hypothesis of Paton
 Agonist and antagonist bind to different site of the 4. Lock and Key Hypothesis
receptor and have opposite pharmacologic action. 5. Affinity

Non- Competitive Antagonist

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1. Hypothesis of Clark
 The pharmacologic effect depends on the percentage
of receptors occupied.
 drug must have affinity for the receptor.
 If the receptors are occupied, maximum effect is
obtained.
Definition of terms
1. Absorption of drugs– is the process of uptake of the
2. Hypothesis of Ariens and Stephenson.
compound from the site of administration into the system
 affinity of drugs to the receptor may lead to degree
circulation.
of effectivity and intrinsic activity.
2. First pass effect – describes the phenomenon whereby
 ineffectiveness may block or inhibit receptors
drugs may be metabolized ( not chemically degraded )
 effectiveness last long as long as the receptor is
after absorption but before reaching the systemic
occupied ( occupation theory ).
circulation. PO, rectal
3. Absolute Bioavailability – is the extent or fraction of drug
3. Hypothesis of Paton.
absorbed upon extravascular administration in
 Effectiveness does not depend upon the actual
comparison to the dose size administered.
occupation by the drug but only obtaining the proper
4. Relative Bioavailability – is the extent of drug absorbed
stimulus.
upon extravascular administration in comparison to the
 Stimulus occurs at the moment the drug attaches
dose size of a standard administered by the same route.
itself to the receptor.
5. Central compartment – is the sum of all body regions
 also known as rate theory.
( organs and tissue ) in which the drug concentration is in
instantaneous equilibrium with that in blood or plasma.
4. Lock and Key Theory
The blood and plasma is always part of the central
 The drug molecule must fit into a receptor as a key into a
compartment.
lock ( intrinsic
6. Concentration gradient – is the difference in the
activity )
concentration in two phases usually separated by a
membrane.
7. Maintenance Dose – is the dose size required to maintain
the clinical effectiveness or therapeutic concentration
according to dosage regimen.

5. Affinity
 Combination of drug molecule with a receptor.
 If a drug has affinity and generates an impulse that
activates the biological system , the drug has intrinsic
activity.

ABSORPTION PROCESS
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1. Principles
 A prerequisite of absorption is that the drug should be Factors that may affect the Drug Rate Absorption Process:
released from the dosage form. 1. Permeation of more than one membrane before it reaches
 release of drug from its formulation , does not ensure the blood capillaries.
that drug molecule is absorbed it depends upon the 2. Capillary density
sorption process. 3. Rate of blood flow at the absorption
 A cell membrane is a semi-permeable structure composed 4. Absorbing surface area
primarily lipids and proteins.
 Drug maybe transported by
1. passive diffusion
2. paracellular transport or vesicular transport
3. convective transport,
4. active transport
 Usually proteins , drugs bound to proteins and
macromolecules do not enter the cell membrane easily .
 Non-polar lipid soluble drugs traverse cell membranes
easily than ionic or polar soluble drugs.

 The intestinal surface area approximates 120-200m2, in

large part because of the presence of macrovilli and
microvilli .
 Percutaneous absorption is significantly more limited
because of the anatomical structure of skin ( surface area
1.73m2).

Transport Mechanisms
1. Passive diffusion
 Transport through a semipermeable membrane.
 Drug must be in aqueous (true) solution at the
absorption site.
 In passing the membrane, the drug molecule
dissolves in the lipid material of the membrane
according to its lipid solubility.
 Most drugs are weak acids or weak bases.
 Unionized moiety is usually lipid soluble.
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Example of compounds which involved in passive diffusion

transport:
a) Weak organic acid
b) Weak organic bases
c) Organic nonelectrolytes: ROH, Urea, amidopyrine
d) Cardiac glycosides in part.
e) ephedrine and metamphetamine
f) epinephrine
g) morphine
h) ampicillin

Passive drug transport across cell membranes involves successive

Partitioning of solute between aqueous and lipid phase as well as
diffusion with respective phases

2. Convective Transport
 Drug molecules dissolved in the aqueous medium at the
absorption site move along with solvent ( shifting of
solvent ) through the pore.
 Ions as well as neutral molecules may pass through the
pore
 drug molecules with MW of spherical compound (150)
and chain –like MW of 400 have been found to be
absorbed by convective transport.
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 Ionized sulfonamides

3. Active Transport
 The drug molecules must be in aqueous solution at the
absorption site.
 Mediated by means of carriers under expenditure of
energy.
 ATP utilization – ATP is broken down in the membrane by
the enzyme ATPase into ADP and PO4 ions – releasing of 3
electronegative charge per molecule of ATP.

Compounds and Drug molecules that are transported via Active

Transport Mechanism:
 Na, K, I, Hexoses, manosaccharides, amino acids, strong
acids and bases, Organic PO4s
 Cardiac Glycosides
 B vitamines
 Testosterone
 Estradiol
 Flourouracil
 Fe
 Methyldopa
 ACE inhibitor
 Gabapentin
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Sodium-Potassium Pump

4. Facilitated Transport
 Drug molecules must be in solution at the absorption site.
 Same as Active Transport
 It does proceed against concentration gradient
 subgroup of Active transport
 Classic example is the absorption of Vitamin B12
fluoroquinolones, NSAID, Epinephrine, dopamine,
guanidine, antiarrhythmics, anithistamines

Human Transporters that have Pharmacokinetics significance:

1. MDR1/P-gp ( Multidrug resistant gene/P-glycoprotein)

 efflux transporter
 Actively pump absorbed drug back into the lumen of the
small intestine. (first pass effect )
2. BSEP/SPGP( Bile salt export pump/Sister P-glycoprotein)
 transport for important route of elimination for
environmental toxins, carcinogens, drugs, and their
metabolites (xenobiotics).
3. MRP1, MRP2, MRP3 ( Multidrug resistance-associated proteins)
 they are critical determinants for the movement of a large
number of commonly prescribed drugs across cellular
barriers.
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 Pinocytosis – is the engulfment of small particles or fluid

volumes.
 Phagocytosis- is the engulfment of larger drug particles or
macromolecules , generally by macrophages
 Endocytosis and Exocytosis- are the movement of drug
macro molecules into or out of the cell

Compounds or substances which involved Vesicular transport:

1. Fatty acids
2. Fats
3. Amino acids
4. Peptides
5. Hormones
6. Proteins
7. Fat-soluble Vitamines ( ADEK )

5. Ion-Pair Transport
 Highly ionized compounds such quaternary ammonium
compounds and sulfonic acids form electrochemically
neutral complexes with cations.
 Drug forms endogenous substances of the GIT, such as
mucin and that these neutral ion-pair complexes are then
absorbed by passive diffusion

1. Combined Absorption model

 Drug might be absorb by more than one translocation
mechanism.
Drugs involve in ion-pair transport shown in vivo or vitro include:  Vitamin B12 is absorbed by active facilitated Transport
1. Ampicillin and partly by passive diffusion.
2. Atenolol  Cardiac glycosides are absorbed by passive diffusion and
3. Chloramphenicol succinate by convective transport.
4. doxorubicin  However, absorption depends on the availability of
5. Metoprolol tartrate transport mechanisms at the site of contact.
6. propranolol
7. Timolol maleate
8. Trospium HCl

6. Vesicular Transport
 Is the process of engulfing particles or dissolved materials
by a cell.
 Vesicular transport is the only transport mechanism that
does not require a drug to be in an aqueous solution to be
absorbed.
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3. Environmental pH – Acid- Base disturbances can affect the

liberation and absorption of weak bases and acids of certain drugs.

Factors that may affect Absorption of drugs:

1. Absorbing Surface
2. Blood Flow
3. Environmental pH
4. Disease States
4. Disease States- disease has the considerable effect upon
1. Absorbing Surface liberation and absorption.
 Area of absorbing is an important determinant of the rate  Example: debridement of the Stratum corneum increases
of absorption. permeability to topical drugs, meningitis increases
 Example the large alveolar surface of the lungs allows permeability of the blood brain barrier , biliary
extremely rapid liberation, absorption of gases , vapors insufficiency decreases the absorption of lipid-soluble
and properly aerolized solution, with some drugs the drugs from the intestine.
liberation and absorption rate may be nearly as fast as
with IV. 5. Interaction with Food, other drugs
 People antidepressant drugs such as MAO- inhibitors
should take not take foods containing tyramine as
hypertensive may occur.
 If a patient is taking two drugs and one of them increases
the effect of the other it is possible that overdose may
occur.
 Example: Codeine + Paracetamol both are analgesics=
overdose
Ciprofloxacin+ furosemide = insoluble precipitate.

Plotting and Interpretation of Drug Dissolution Data ( calculation )

 Drug Dissolution data are obtained in vitro for tablets or
capsules using the USP Dissolution Test, which defines the
2. Blood Flow apparatus and methods to be used. The data obtained
 Once the drug reaches the blood diffusion is not important may be presented in tabular form and depicted
to transport and the rate of blood flow determines. graphically.
 The blood flow velocity in a capillary is about 1mm/sec
which is 100x than the mean net velocity of the drug
molecules 1mm away from their injection site.
 The velocity of blood flow is even faster in the large
vessels .
 This true for IV infusion.
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Area under the curve ( AUC )- is considered representative of the

total amount of drug absorbed into the circulation following the
administration of a single dose of that drug.

 If a perpendicular line is drawn from the concentration at

1hr ( 7mg/L ) down to the time axis, then the area bound
to zero time and 1 hr is a trapezoid with area given by the
product of average concentration and time interval.
 The average concentration is obtained by adding the
concentration at the beginning and end of the time
interval and dividing by 2 times multiply it to the time
interval.
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Example Calculations of Bioavailability and Bioequivalence:

 If drug dissolution or drug absorption studies
demonstrates consistently that a portion of a drug
substance in a dosage form is available for biologic
absorption, the drugs availability factor (F)- which
represents the decimal percentage of a drug substance
available may be used to calculate bioavailability.
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“Bioequivalent” amounts of bioequivalent Dosage form.

 The bioavailability of a given drug substance may vary
when in different dosage forms or in the same dosage
form from a different manufacturer. Thus it may be
desired to calculate the equivalent doses for two
bioequivalent products.

1. If the bioavailability factor ( F ) for a drug in a dosage form is 0.60,

how many milligrams of drug would be available for absorption from
100mg tablet of the drug?

2. If the bioavailability factor ( F ) for a 100mg tablet of a drug is 0.70

compared with the bioavailability factor 1.0 for an injection of the
same drug, how many ml of the injection containing 40mg/ml would
Take note the bioequivalent may be considered if the ratio is
be bioequivalent to the tablet.
between 0.8 to 1.25 or 80% to 125% of the reference drug
3. If 5ml of an elixir containing 2mg/ml of a drug is bioequivalent to
Problem:
a 15 mg tablet having a bioavailability factor of 0.60 , what is the
1. AUC values of penicillin up on i.v. administration of 50mg and oral
bioavailability factor of the elixir?
administration of 100mg tablet were found to be 70mg.hr/L and
90mg.hr/L respectively.
4. If 500mg of a drug are administered orally and 300mg are
absorbed in the circulation, calculate the bioavailability.
Calculate:
1. Absolute Bioavailability of penicillin
5. A drug is 40% bioavailable by the oral route and 58% bioavailable
2. Relative Bioavailability of penicillin from tablet based on
by the transdermal route. If a patient is taking 2.5mg oral dose twice
penicillin suspension whose dose is 100mg and AUC is 95.
a day and is switched to the counterpart 2% ointment, how many
grams of the ointment should be administered to provide the
2. AUC values of Amoxicillin up on i.v. administration of 100mg and
equivalent dose of the drug.
oral administration of 250mg capsule were found to be 75mg.hr/L
and 94mg.hr/L respectively.
6. If 5ml of an elixir containing 5mg/ml of a drug is bioequivalent to
Calculate:
a 30 mg tablet having a bioavailability factor of 0.70 , what is the
1. Absolute Bioavailability of Amoxicillin
bioavailability factor of the elixir?
2. Relatively Bioavailability of Amoxicillin from capsule based
amoxicillin suspension whose dose is 250mg and AUC is
7. If the bioavailability factor ( F ) for a 250mg tablet of a drug is 0.65
96.
compared with the bioavailability factor 1.0 for an injection of the
same drug, how many ml of the injection containing 80mg/ml
3. AUC values of Cefuroxime up on i.v. administration of 400mg and
would be bioequivalent to the tablet if 60% of the injection is only
oral administration of 500mg capsule were found to be 79mg.hr/L
available .
and 97mg.hr/L respectively.
Calculate:
8. If the AUC for an oral dose of a drug administered by tablet is
1. Absolute Bioavailability of Cefuroxime
4.5mcg/ml, and intravenous dose is 11.2mcg/ml, calculate the
2. Relative Bioavailability of Cefuroxime from capsule-based
bioavailability of the oral dose of the drug.
Cefuroxime suspension whose dose is 250mg and AUC is
93
9. If the AUC for an oral dose of a drug administered by tablet is
5.8mcg/ml, and intravenous dose is 12.6mcg/ml, calculate the
bioavailability of the oral dose of the drug.
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BLOOD PERFUSION

Perfusion – process of delivery of blood to a capillary bed in the

biological tissues.
 Blood, perfusing tissues delivers and removes substances.
 Accordingly viewing any tissue as a whole, the movement
of drug through the membrane cannot be separated from
perfusion considerations.
 When movement through a membrane readily occurs , the
slowest or rate limiting step in the entire process becomes
perfusion not permeability.
 The initial rate of movement of drug into the tissues is
determined by the rate of its delivery which depend on
blood flow.
 Perfusion is usually expressed into units of milliliters of
blood per minute per gram of tissues
 Perfusion rate of tissues varies from approximately
1. What is the absolute bioavailability of the drug from the 10ml/min per gram of tissue for lungs down to values of
capsule? only 0.025ml/min per gram of tissue or fat or resting
2. What is the absolute bioavailability of the drug from SR muscle.
tablet?  All other factors remaining equal , well- perfused tissues
3. What is the relative bioavailability of SR tablet against oral take up a drug much more rapidly than do poorly
solution? perfused tissues.
4. Which formulation shows better bioavailability ?

More over as the subsequent analysis show, there is a direct

correlation between tissue perfusion rate and the time required to
distribute a drug to a tissue.

 The rate of presentation in the tissues is the product of

blood flow (Q) and arterial blood concentration CA that is
the emergent venous blood concentration.

Effects of pH and Pka

 Most of the drugs are either weak acids or weak bases.
Therefore they are part ionized and part unionized.
 The ionized portion is charged, which attracts water
molecules, thus forming large complexes.
 These complexes cannot cross the membranes because
they are less lipid soluble. This is why the ionized part of
the drugs cannot cross the membrane. Drugs are better
absorbed in unionized form.
 The un-ionized form is usually lipid soluble (lipophilic) and
diffuses readily across cell membranes.
 The ionized form has low lipid solubility (but high water
solubility—ie, hydrophilic) and high electrical resistance
and thus cannot penetrate cell membranes easily.
 23

 The proportion of the un-ionized form present (and thus Intestinal Motility :
the drug's ability to cross a membrane) is determined by  Normal peristaltic movement mix the contents of the
the pH and the drug's pKa(acid dissociation constant). duodenum bringing drug particles into intimate contact
 The pKa is the pH at which concentrations of ionized and with the intestinal mucosal cells.
un-ionized forms are equal.  In the case of high motility in the GIT, as in diarrhea the
drug has a very brief residence and less opportunity for
 For a weak base with a pKa of 4.4, the outcome is reversed; adequate absorption.
most of the drug in the stomach is ionized. Theoretically,
weakly acidic drugs (eg, aspirin ) are more readily
absorbed from an acid medium (stomach) than are weakly
basic drugs (eg, quinidine ).
 However, whether a drug is acidic or basic, most
absorption occurs in the small intestine because the
surface area is larger and membranes are more
permeable.
 Example: Phenobarbital (acidic drug)
 Increased pH leads to increased ionization leads to
increased water solubility and decreased solubility in
other organic solvents.
 Example: Procaine HCl (basic drug)
 Increased pH leads to decreased ionization leads to
decreased water solubility and increased solubility in
other organic solvents.

Gastric Emptying Time

 a swallowed drug rapidly reaches the stomach. Eventually,
the stomach empties its content into the small intestine. Route for administration:
 Because the duodenum has a greatest capacity for the
absorption of drugs from the GI tract, a delay in GET for -Time until effect-
the drug to reach the duodenum will slow the rate and 1) intravenous 30-60 seconds
possibly the extent of drug absorption, thereby prolonging 2) intraosseous 30-60 seconds
onset time of the drug. 3) endotracheal 2-3 minutes
4) sublingual 3-5 minutes
Why is gastric (stomach) emptying time so important? 5) intramuscular 10-20 minutes
 The longer a supplement stays in the stomach, the longer 6) subcutaneous 15-30 minutes
the time before absorption can begin, because no 7) rectal 5-30 minutes
appreciable absorption occurs from the stomach. 8) ingestion 30-90 minutes
 Often the rate-limiting step in the absorption process is 9) transdermal (topical) variable (minutes to hours)
the time it takes for the tablet or capsule to disintegrate,
and the nutrients to dissolve and equilibrate to the proper Physico-chemical factors altering biological performance of drugs:
(isotonic) state to leave the stomach. 1. Particle size
 When all this has been completed — up to 40 minutes 2. Co-solutes and complex formation
after ingestion — the diluted, acid-attacked nutrients can a. Salting-out
enter the small intestine for absorption. b. salting-in
c. Clathrate Formation
d. Solid-in-solid Solution Complex
3. Polymorphism
4. Chemical Variation
5. Viscosity
6. Manufacturing Factors

1. Particle size
 with decreasing particle size, surface area increases, thus
increasing the area of solid matter being expose to the
dissolution media and hence dissolution rate increases
( becomes more rapid )
 decreasing particle size , surface area increases
 Example of drugs for which therapeutic differences have
been found depending on particle size:
o amphotericin, aspirin, chloramphenicol,
floucinolone, acetonide, griseofulvin,
nitrofuratoin, tolbutamide, phenylbutazone,
phenobarbital, phenothiazine, prednisolone,
procaine, penicillin, reserpine, spironolactone.
 The smallest particle size used are in the range of 1-10μm.
 24

 Particle size reduction is not universal answer for all drugs d. Solid-in- solid
of low solubility.  If a drug is dissolved in a melt of mannitol
or a mixture of mannitol and other
2. Co-solutes and complex formation- This is true only for all carbohydrates of succinic acid for example
drugs of low solubility. and the mixture is solidified or crystallized
a solid-in- solid solution is obtained where
a. Salting-out drug is monomolecular dispersion
 If an electrolyte is added in solid form to a
solution of an organic non electrolyte, the ions
of the added electrolyte require water for their
hydration and thereby reduce the amount of
water available for the solution of non-
electrolyte will precipitated- salting out

b. Salting- in Drugs used in solid – in solid solutions are:

 occurs when either salts of various organic acids or Griseofulvin , Chloramphenicol ,Aminobenzoic acid, Antihistamines
organic-substituted NH4 salts are added to aqueous + melts of urea
solutions of non-electrolyte. True for Naproxen Prednisone + polyvinylpyrrolidone
sodium and Procaine + ethanol + water co-solvent.

3. Polymorphism- is the ability of the drug to exist in more than one

crystalline form.
 Polymorphism exist only in the solid state.
 e.g. Chloramphenicol palmitate has three polymorphs A, B
and C. The B -form shows best bioavailability and A form is
virtually inactive biologically.
e.g. Polymorphic form-III of riboflavin is 20 times more
water soluble than the form-I.
 Due to aging of dosage forms containing metastable
forms of the drug results in the formation of less soluble,
stable polymorph.
e.g. more soluble crystalline form-III of cortisone acetate
converts to less soluble form-V in an aqueous suspension
c. Clathrate formation
resulting in caking of solid.
 Formed if a substance is capable of forming channels,
or cages which can take up another substance into
4. Chemical variation- are made for two reasons either to change
the intraspace of the structure.
the structure of the active compound in order to increase
pharmacologic response or to maintain the basic structure but
change solubility by formation of either salts , esters, ethers or
complexes.
 Example:
 Chloramphenicol and Erythromycin are absorbed
from the GIT in form of base , however they are
unstable in the gastric fluid. Chloramphenicol esters
dissolve at higher pH of the small intestine

5. Viscosity
 Increasing their viscosity prolongs the time of diffusion of
solvent molecules to the surface of solids. Disintegration
and dissolution of tablets are decreased with increasing
viscosity.
Clathrate forming substance:
 gallic acid, urea, thiurea, amylose and zeolite The experiments were designed to allow recognition of possible
effects due to complex formation and evaluation of the effect of
Drugs used in clathrates: viscosity on (a) the rate of movement of drug molecules to the
 Vit. A, Sufathiazole, chloramphenicol, reserpine absorbing membranes and (b) the rate of gastrointestinal transit of
the solutions. It was found that both a and b were decreased with
increasing viscosity , (Gerhard Levy and William Jusko 2000.)
 25

6. Manufacturing Factors- Many units used in manufacture of drug

products may decrease biological performance of drugs. Eg. Increase
the amount of tablet binders then it will prolong LADMER process.

Lipid/water partition coefficient

 The lipid/ water partition coefficient denotes the ratio of
the concentration of a drug in two immiscible or slightly
miscible phases.
 Lipid soluble drugs (having higher lipid water partition
coefficient) are more retained in the body while water
soluble drugs are easily excreted out.

 Distribution is the movement of a drug inside the body

once the drug has reached the blood. Blood carries the
drug throughout the body and also to its sites of action.
 First, distribution is affected by the blood flow rates to
certain organs. When an organ has a high blood flow rate
such as in the heart, liver, and kidneys, the drug is
distributed quickly.
 However, there are some tissue membranes that are
highly selective in allowing drugs to penetrate through. For
example, the blood-brain barrier limits drug access to the
brain.
 Lastly, protein binding can affect distribution as well. Most
drugs bind to proteins in the blood plasma, forming what
is called a complex. Because these complexes are large, it
prevents the drug from entering its sites.

 So, only free or unbound drugs can move through the

tissue membranes. Furthermore, some drugs with a
stronger binding capacity can displace a weaker bound
 26

drug from a protein, making the weakly bound drug not FACTORS AFFECTING DRUG DISTRIBUTION:
bound anymore.
 Diazepam is considered to be highly lipophilic tranquilizer Related to drug molecules:
having faster effect compare with the lorazepam but this 1. Lipid Solubility
lorazepam has a longer duration of action because it 2. Molecular size
remains at the site of action. 3. Degree of Ionization
4. Cellular binding
Kinetics of protein binding 5. Duration of Action
 The kinetics of reversible drug – protein binding for a
protein with one simple binding site can be described by 1. Lipid Solubility
the law of mass action.  Greater the lipid solubility, more is the distribution and
 P+D is reversible PD vice versa.
 From the complex and the law of mass action , an
association constant can be expressed as the ratio of the
molar concentration of the products and the molar
concentration of the reactants. This equation assumes
only one binding site per protein molecule,
 The extent of the drug – protein complex formed is
dependent on the association binding constant Ka . The
magnitude of Ka yields on the degree of protein binding.
 Drugs strongly bound to protein have a very large Ka and
exist most as the drug – protein complex . With such drugs
, a large dose maybe needed to obtain a reasonable
therapeutic concentration of free drug.
 Most kinetic studies in vitro use purified albumin as a
standard protein source, because this protein is
responsible for the major portion of plasma drug - protein
binding .
 Experimentally, both free drug (P) and the protein bound 2. Molecular size
(PD) , as well as the total protein concentration (P) + (PD) ,  Larger the size, less is the distribution. Smaller sized drugs
may be determined. are more extensively distributed.

to study the binding behavior of drugs, a determined ratio (r) is

defined as:

Because of moles of drug is (PD) and the total moles of protein is (P)
+ (PD) this equation becomes:

3. Degree of Ionization
 Drugs exist as weak acids or weak bases when being
According to above (PD) = Ka (P) (D) ; but substitution into equation distributed. Drugs are trapped when present in the ionized
above , the following expression is obtained: form, depending upon the pH of the medium. This fact can
be used to make the drug concentrated in specific
compartments.

 This equation describes the simplest ratio situation, in

which 1 mole drug binds to 1 mole of protein in 1:1
complex.
 27

4. Cellular binding
 Drugs may exist in free or bound form. Bound form of
drugs exists as reservoirs. The free and bound forms co-
exist in equilibrium. Cellular binding depends on the
plasma binding proteins.
 Tissue binding:
 Different drugs have different affinity for different cells.
All cells do not bind the same drugs.

5. Duration of Action
 The duration of action of drugs is prolonged by the Factors related to the body
presence of bound form while the free form is released. 1. Vascularity
This leads to a longer half life and duration of action of 2. Transport Mechanism
drug. 3. Blood Barriers
4. Placental barrier
5. Plasma Binding Proteins
6. Disease states
7. Drug reservoir
8. Volume of distribution

1. Vascularity
 Most of the blood passes through the highly perfused
organs (75%) while the remaining (25%) passes through
the less perfused areas.
 Therefore, most of the drugs go first to the highly perfused
areas. They may get bound to these organs. They are then
redistributed to the less perfused areas like the skin and
the skeletal muscles. This phenomenon is common among
the lipid soluble drugs.
 Example includes thiopental sodium which is used as
general anesthetic. When given, it goes to the brain
Half-life is the amount of time required for a quantity to fall to half producing its effects. It is then redistributed to the less
its value as measured at the beginning of the time period perfused organs. Because of high lipid solubility, it is
 The RBC binding sites for drugs are : intracellular proteins, accumulated in the fatty tissue for longer duration. Thus
hemoglobin, carbonic anhydrase, cell membrane and the clearance of the drug is slow, producing prolonged
ATPase. period of drowsiness (up to 24 hours).
 RBC binding to carbonic anhydrase ( acetazolamide )
 RBC to oxyhemoglobin ( phenothiazines ) 2. Transport Mechanism
 RBC to nucleoside transport system ( benzodiazepines )  Different drugs are taken up by different compartments of
 Binding to erythrocytes may be age dependent the body differently. Lipid soluble drug move by passive
(meperidine ) concentration dependent ( diazepam ). transport which is non specific. Active transport occurs
only where carrier proteins are present.

3. Blood Barriers
 Different blood barriers exist. Blood brain are barrier that
separate brain tissues from out side environment.

 Transporters:
 Certain efflux pumps or transporters exist through which
drug can be effluxed as well. Example includes p-
glycoprotein.
 28

 Disruption:  Binding should always be reversible and the percentage

 Disruption of barrier may occur, e.g. by inflamed bound remained constant with the exception of
meningitis. Drugs may pass which might be toxic as well as salicylates, valproic acid and tolbutamide.
beneficial i.e. during meningitis penicillin can pass which
has beneficial effects.

 Serum albumin is not only the proteins involved. The ἀ1-

acid glycoprotein binds drugs that are cationic at
4. Placental barrier physiological pH such as quinidine, alfentanyl,
 Placenta is the membrane separating Fetal blood from the disopyramide, lidocaine, propranolol, imipramine, and
Maternal blood. erythromycin.
 It is made up of Fetal Trophoblast Basement  It is known that stress of a critical illness , pregnancy,
Membrane and the Endothelium. cancer, and inflammatory conditions such as crohn’s
 Mean thickness in early pregnancy is (25 µ) which disease, rheumatoid arthritis, hepatic cirrhosis can boost
reduces to (2 µ) at full term. levels of ἀ1- acid glycoprotein and lead to increase binding
of these drugs.

 Many drugs having mol. wt. < 1000 Daltons and moderate
to high lipid solubility e.g. ethanol, sulfonamides,
barbiturates, steroids, anticonvulsants and some
antibiotics cross the barrier by simple diffusion quite
rapidly .
 Nutrients essential for fetal growth are transported by
carrier mediated processes

5. Plasma Binding Proteins

Many proteins exist in the plasma. Plasma binding proteins include:
 Albumin
 Albumin is the most abundant plasma protein. It has
higher affinity for acidic drugs but the capacity is low.
Only two sites are present for binding drug molecules. Competition b/w drug for binding site (displacement interaction )
 However, albumin can bind a large number of basic  When two or more drug present to the same site ,
drugs but has lower attractive forces. Its capacity for competition b/w them for interaction with same binding
binding basic drugs is more but the affinity is less. site .
 Glycoproteins  If one of the drug (A) is bound to such a site , then
 Alpha glycoproteins mainly bind basic drugs. Their administration of the another drug (B) having high affinity
levels are increased during stress, trauma and for same binding site result in displacement of drugs (A)
surgery. It is during these times that their more from its binding site . This type of interaction is known as
amounts are required. displacement interaction .
 Where drug (A) here is called as the displaced drug and
 Most weakly acidic drugs bind to albumin to a varying drug (B) as the displacer .
degree.  Eg. Phenylbutazone displace warfarin and sulfonamide
 Two binding sites are involved : site 1 drugs such as from its binding site
warfarin and phenylbutazone and site 2 diazepam and
Ibuprofen. Increased amount of free drug may result in toxicity.
 Take note drugs binding at the same site will displace each  Displacement of tolbutamide by sulfonamides 
other in a competitive fashion. hypoglycemic
 Displacement of bilirubin , salicylates  kernicterus
 29

 Displacement of warfarin by phenylbutazone  Summary:

hemorrhage .

6. Disease States
 Different diseases affect the distribution of drugs. Renal
diseases cause hypoalbuminemia. Due to less proteins,
toxic levels of free drugs may be present. Uremic by-
products are also produced which compete with drugs.
 Hepatic diseases cause decreased synthesis of proteins
causing hypoalbuminemia. Free drugs may be present in
toxic levels and bilirubin by products increase as well.
 Thus drug , whose doses have to be adjusted to produced
desired effects (may be reduced even to half).

Compartment Models

7. Drug Reservoirs
Drugs are stored and are released slowly which affects their
pharmacokinetics and pharmacodynamics. Drug reservoirs include: One compartment model
1. Plasma proteins  All drugs initially distribute into a central compartment
2. Liver (Vc) before distributing into the peripheral compartment
3. Adipose (Vt). If a drug rapidly equilibrates with the tissue
4. Bone compartment, then, for practical purposes, we can use the
5. Placenta much simpler one-compartment model which uses only
6. Breast milk one volume term, the apparent volume of distribution, Vd.
7. Transcellular fluid reserves
8. Other body tissues- eye, kidneys, skeletal muscles, skin

8. Volume of Distribution
 The apparent or hypothetical volume in the body into
which a drug distributes.

Compartments:
 First of all the drug enters the plasma which is
approximately 4 liters. Heparin is a large molecular
drug, it does not cross blood vessel lining, thus
volume of distribution is less.
 Gentamicin, an antibiotic leaves the plasma to enter
the interstitial fluid, its volume of distribution is
approximately 14 liters. Serum level plot for a 2-compartment model
 Some drugs like ethanol pass from the interstitial fluid Yields a biphasic line when using a log scale on the y-axis.
to the intracellular fluid and enter the fluid of the
cells, thus have the volume of fluid approximately 42
liters. Summary:
A one-compartment model may be used for drugs which rapidly
equilibrate with the tissue compartment, e.g, aminoglycosides.
 A two-compartment model should be used for drugs which
slowly equilibrate with the tissue compartment, e.g,
vancomycin.
 A log scale plot of the serum level decay curve of a 1-
compartment model yields a straight line.
 30

 A log scale plot of the serum level decay curve of a 2- Metabolism

compartment model yields a biphasic line.  Also called ( biotransformation) refers to the changes that
Failure to consider the distribution phase can lead to drugs and other foreign chemicals ( xenobiotics ) undergo
significant errors in estimates of elimination rate. in the body leading to the formation of different
metabolites with different effects.
Effects of drugs on Cardiac Output
1. Cardiac Output- is the amount of blood in liters pumped
by the heart per minute.
2. The drugs responsible for a cardiac output reduction are
called beta-adrenoceptor blocking drugs; these drugs are
very effective in reducing the blood pressure and have,
moreover, a protective effect on the heart.
3. Their principle is to decrease the cardiac output by
decreasing the frequency of the heart. Thus, these drugs
must be supervised regularly because they slow down the
heart rate in a very significant way.

Principal beta-blockers are: the atenolol, the acebutalol, the

propranolol, the celiprolol, the metoprolol, the pindolol, the nadolol,
the carteolol, the esmolol, the timolol, the penbutolol, the
bisoprolol, and the betaxolol.
Metabolism serves 3 principles:
1. To supply energy for body functions and maintenance
2. To breakdown ingested compounds. Eg catabolism to
simpler structure and biosynthesis of more complex
molecules eg. Anabolism usually requiring energy
3. For the conversion or biotransformation of foreign
compounds to more polar, water-soluble, and ionized
structures which can be eliminated more easily.

Regional Blood Flow: Drug metabolism

 Drug metabolism and renal excretion represent the two
Regional Blood flow limited in drug distribution main pathways for clearing the drug from the body.
 Initially, liver, kidney, brain, and other well-perfused  Drug metabolism takes place for the most part in the liver,
organs receive most of the drug; delivery to muscle, most but other sites may be involved including the GI wall, lung,
viscera, skin, and fat is slower, and this second distribution brain, kidney and in plasma.
phase may require minutes to several hours before the  For most drugs metabolism is a detoxification or
concentration of drug in tissue is in equilibrium with that detoxication process making lipid-soluble drugs more
in blood. water soluble so that they are excreted in urine more
readily.
Thus, tissue distribution is determined by the partitioning of drug
between blood and the particular tissue. Lipid solubility and Glucuronic acid (C6H10O7)- a derivative of glucose, is produced in the
transmembrane..." liver of humans and most animals. It is a highly soluble compound
1. Ultra-short acting barbiturates that can bind to substances such as hormones, drugs, and toxins to
1. Brain is saturated FIRST facilitate their transport around the body.
2. Muscle is saturated LATER  In this way glucuronic acid is largely responsible for the
2. Patients wake up because the muscle keeps soaking up elimination of poisonous substances or toxic substances.
drug (not because drug is metabolized)  Glucuronidation is the addition of glucuronic acid to a
1. Not all barbiturates substrate. Glucuronidation is often involved in xenobiotic
2. Does not apply to gas anesthetics metabolism of substances such as drugs, pollutants,
bilirubin, androgens, estrogens, mineralocorticoids,
glucocorticoids, fatty acid derivatives, retinoids, and bile
acids.
 Detoxication should not be use as collective term for drug
metabolism because metabolic products of some drugs
are more toxic or more pharmacologically active than the
parent molecule.
 For example metabolism of drugs like:
 Metabolism of phenacetin, pyridine, sulfadiazine,
sulfamerazine results in more toxic metabolic products
like analogs of purines and pyrimidines for carcinostatic.
 2. Prontosil forms sulfanilamide
 3. Imipramine forms desmethylimipramine
 4. ἀ- methyldopa forms ἀ-methylnorepinephrine
 31

Drug metabolism is very complex.

 Usually drug metabolites are more water-soluble than the
parent structures because derivatives contain more
functional group or they are conjugated with hydrophilic
substances.
 There are active metabolites of drugs which are less
soluble in water than the parent compounds.

Example: p-chlorophenaceturic acid- a metabolite of p-

chlorophenylacetic acid, m-acetonamidobenzoic acid produce
from m- aminobenzoic acid, N-acetylsulfanilamide a
metabolite of sulfanilamide.

Pathways of Drug Metabolism:

 The principal site of metabolism
 32

 Less important are the:

Oxidation
 addition of oxygen and/or the removal of hydrogen
 Mostly occurs in the endoplasmic reticulum

Reduction
 addition of hydrogen or the removal of oxygen
 occurs GI tract because of the normal flora.

Hydrolysis
 addition of water with the breakdown of the molecule
 Mostly occurs in blood plasma (esterases) and liver

Phase 1 Drug Metabolism ( Non-synthetic )

 catabolic in nature involves oxidation, reduction, and
hydrolysis.

Metabolizing enzymes occur in the soluble, mitochondrial, or the Cytochrome P450 exists in multiple isoforms or families:
microsomal fractions.
 Metabolism also takes place in the bloodstream to some
extent because enzymes are produced by the cell spill over
the extracellular fluid.

Drug metabolism reactions are divided into Phase 1 or non-

synthetic reactions and Phase 2 synthetic reactions.
 The most common drug metabolism reactions comprise
oxidation, reduction, hydrolysis and conjugation.
 The extent of formation of the different metabolites
depends on the relative rate of reaction.
 In Pharmaceutical Biochemistry--- Drug conjugation “the
union of a drug or toxic substance with a normal
constituent of the body, such as glucuronic acid, to form
an inactive product that is then eliminated”.

 Most of the oxidation reactions are catalyzed by

microsomal enzymes requiring oxygen and NADPH (
nicotinamide-adenine-dinucleotide-phosphate )
 The formation of double conjugates is rare because a
compound once conjugated is easily excreted.
33
 34

Reduction:
Chloral hydrate Trichloroethanol
Chloramphenicol  amino derivative
Dimethyl sulfoxide  Dimethyl sulfide

Hydrolysis:
Aspirin  Salicylic acid  Acetic acid
Procainamide  p-Aminobenzoic acid  Diethylaminoethylamine
Isoniazid  Isonicotinicacid  NH2NH
Phenacetin  Phenetidin  Acetic acid

Phase 2 Drug Metabolism ( Synthetic )

 anabolic reactions such as glucuronidation and sulfation
where the metabolite is conjugated covalently with a more
 Some drugs undergo metabolism at both hepatic and water soluble compounds.
extrahepatic sites such as the liver, gut or plasma. Example  Many drugs undergo both processes . Example: phenytoin
: Fentanyl. undergoes extensive and complex metabolism at least 8
phase 1 and 2 phase 2 metabolites identified by

Example of Phase 1 ( non- Synthetic Reaction ) of biotransformation

Oxidation:
1. Hydroxylation of aromatic rings
Acetanilide  N-acetyl-p-aminophenol
Phenobarbital  p- Hydroxyphenobarbital
Phenylbutazone  Oxyphenbutazone
Salicylic Acid  Gentisic acid
Chlorpromazine  7- hydroxychlorpromazine

2. Oxidation of side chain

Chloral hydrate  Trichloroacetic acid
Meprobamate  Hydroxymeprobamate

3. N-Dealkylation
Aminopyrine  4-Aminoantipyrine + HCHO
Mephobarbital  Phenobarbital + HCHO
Chlorpromazine  Desmonomethylchlorpromazine
Codeine  Normeperidine

4. O-Deakylation
Phenacetin  N-Acetyl-p-aminophenol + CH3CHO
Codeine  Morphine
 35

METABOLIC PROCESSES IN THE NEWBORN AND INFANT:

Take note: The high energy for acetylation is acetyl co-enzymeA. The
reaction is catalyzed by N-acetyltransferase

Phase 2 ( Synthetic Reactions )

1. Glucuronic acid conjugation

Chloramphenicol  Chloramphenicol glucuronide
Sulfanilamide  Sulfanilamide glucuronide
Salicylic acid  o- Carboxyphenyl glucuronide

2. Methylation
Histamine  N- Methylhistamine
Norepinephrine  Normetanephrine

3. Acetylation
INH  Acetyl-INH
Sulfonamide  N- Acetylsufonamide

Biotransformation from Inactive or Active Parent Drugs to Active or

more active Metabolites:
36
 37

DRUG ELIMINATION, CLEARANCE AND RENAL CLEARANCE

Objectives:
1. Describe the main routes of drug elimination from the
body.
2. Describe the processes for renal drug excretion and
explain which renal excretion process predominates in the
kidney for a specific drug, given its renal clearance.

Excretion of drugs is the final elimination from the body.

Drugs may be eliminated from systemic circulation by different
pathways:
1. Urine
2. bile
3. intestine
4. saliva
5. alveolar air
6. sweat
7. milk.

Renal Excretion of Drugs:

 Measurement : 10-12cm in length & 5-6cm width.
 weight: 120-200grams
 Main function: to eliminate substances from the blood to
maintain the internal melieu.
 38

The functional unit of the kidney is the nephron. There are five Glomerular filtration is influence by:
parts of the nephron: 1. Blood flow through the kidney
1. The glomerulus which is the blood kidney interface, 2. If the Na content increases in the distal tubuli. The kidney
plasma is filtered from capillaries into the Bowman’s secretes the enzyme renin in the blood.
capsule.
2. The proximal convoluted tubule which reabsorbs most of
the filtered load, including nutrients and electrolytes.
3. The loop of Henle which, depending on it’s length,
concentrates urine by increasing the osmolality of
surrounding tissue and filtrate.
4. The distal convoluted tubule which reabsorbs water and
sodium depending on needs,
5. The collecting system, which collects urine for excretion .
There are two types of nephrons, those localized to the
cortex, and those extending into the medulla. The latter
are characterized by long loops of Henle, and are more
metabolically active.

Renal Clearance of a drug – is the volume of blood that is cleared of

the drug via kidney per min.
 When the compound is filtered only by the glomerulus and
is not otherwise acted by the kidney, the clearance is equal
to the GFR.

Tubular Transport of Drugs:

 Glomerular filtration – is an essential part of the urine
formation:
 The final composition of urine actually excreted depends
largely on the transport of solutes and water across the
renal cells of the tubuli.
 Transport mechanism involved is passive diffusion or by
active transport.
 Glomerular filtration of solutes is limited by their
 the transfer of metabolites from the lumina of the tubuli
molecular size and shape.
to efferent capillaries and vice versa
 High MW are not freely filtered.
 In passive diffusion transfer in either direction depends on
 kidney is practically free of proteins having MW of 60,000-
the principles of diffusion.
70,000 or more
 It is assume that only unionized form of a drug can pass
 Normal renal blood flow is 1200ml/min , this means that
the membrane. Urinary pH in humans varies between pH
approximately 0.01mm3 of blood flows through the
4.8 & 7.5 with an average of pH 5.8.
glomerulus per second.
 39

 In the case of active transport, the general principles apply

 Active transport occurs from efferent arterioles into the
lumen of the tubuli (secretion)and also from the tubuli
back into the bloodstream (active re absorption).
 Most of active secretion occurs in the proximal tubuli.
 secretion of hydrogen ions and ascorbic acid for
acidification of urine occurs in the distal tubule.

Renal excretion of Drugs and Metabolites

 Many drugs are excreted via the kidney in unchanged
form, many drugs are more or less excreted in the form of
one or more metabolites.
 Determination of pharmacokinetic parameters of the
parent molecule from urinary excretion studies is
permissible only if at least 10% of the drug is excreted into
urine in unchanged form.

Drugs Renally Excreted in unchanged form:

 Barbital, digoxin, flourescein, hexamethonium, kanamycin,
streptomycin, gentamycin, vancomycin.

Drugs Renally Excreted in largely unchanged form:

1. Amphetamine -30%
2. Ampicillin 40%
3. Atropine 20-50%
4. Neostigmin - 40%
5. Procainamide – 50%
6. Penicillin – 60-80%
7. Tetracycline – 60%

Factors Influencing Renal Clearance

1.Age and Sex
2. Disease
 in the kidney (nephritis, pyelonephritis, nephrosclerosis,
and renal failure ) and cardiac diseases ( cardiac failure),
renal clearance is reduced.
3. Rates of filtration depend on:
 Volume filtered in the glomerulus
 Unbound drug concentration in plasma (plasma protein-
bound drug is not filtered)
 40

Pharmacogenetics of Drug-Metabolizing Enzymes and Transporters

 The presence of drug-metabolizing enzymes and
transporters in the cortex of the human kidney can
influence both the renal clearance and total plasma
clearance of selected xenobiotics that are substrates for
these proteins.
 P-gp is the most important transport protein in the kidney
in regulating tubular secretion.

Following drugs that inhibit either CYP3A5 or P-gp expression and

would be expected to inhibit tubular secretion and thus reduce the
renal clearance of drug substrates for these proteins:
 Macrolide antibiotics
 Azole antifungal agents
 Quinidine
 Verapamil

Threshold of Substances Excreted into Urine

 Many substances filtered through the glomeruli are
reabsorbed from the tubuli by active transport as long as
there are carriers available.
 The blood level up to which the substance is returned to  Biliary excretion is of importance for drugs that are poorly
the bloodstream by active transport is called the threshold absorbed from the intestines because they are completely
level. or nearly completely ionized at the pH of the intestinal
 an example is glucose. Up to about 300mg glucose/100ml contents.
blood the glucose filtered through the glomeruli is more or  Compounds that are ionized in blood and tissue fluid
less completely reabsorbed ( threshold level ) usually shows biliary and renal excretion.

Biliary Excretion of Drugs Liver Function testing with Bromosulphthalein

 The liver is the largest organ in the body.  BSP is used for determination of the secretory function of
 Situated to the right of the stomach and is covered with the liver.
connective tissue.  Pathological results could be either damage to liver of
 it has a wide range of functions, including detoxification, parenchymal tissue or cause by icterus.
protein synthesis, drug biotransformation & drug excretion  Formula:
and production of biochemicals necessary for digestion.

No liver damage : up to 5 % BSP retention

Mild liver damage : 5 – 25% BSP retention
Severe liver damage: 25-75% BSP retention
Very severe liver damage : 75 – 100% BSP retention
 41

Once drug is absorbed in the circulation. A portion of the total drug

concentration is bound to plasma proteins ( albumin ) and the
portion remains unbound or free.

CT = Total drug concentration

Cu = unbound drug, free drug, detached drug
CB = bound drug, attached drug
Alphq (ἀ ) = fraction of unbound drug in the plasma
compared with the total plasma drug concentration ,
bound and unbound

Formula for computation of ἀ

 CT = Cu + CB
Cu
 ἀ=
CT
Take note:
ἀ > 0.9 is little bound
ἀ < 0.2 is highly bound
2. Salivary Excretion of Drugs
 Drugs may pass from the circulatory system into the Practice problem:
gastrointestinal tract by different routes. 1. If the alpha ἀ value for the drug digoxin is 0.70, what
 The major pathway is by biliary secretion , but drugs may would be the conc. of free drug in the plasma if the total
also pass directly into the GIT from the bloodstream, plasma conc. of the drug were determined to be
depending on the drug’s pka and environmental pH. 0.7ng/ml?
 pH of saliva is 5.8 to 8.4 2. What is the ἀ for a uremic patient with a reported
 unionized drug are excreted through saliva by passive phenytoin conc. of 4mcg/ml and free plasma conc. of
diffusion 1.0mg/ml?
 the bitter after taste of the patient is the indication of 3. The ἀ value for a drug in the blood is 0.9 equating to
drug is excreted. 0.55mg/ml of free drug. What is the concentration of the
total drug in the blood ?
3. Salivary Recycling of Drugs 4. What is the total drug plasma concentration and ἀ value
 Drugs excreted in the saliva undergo cycling in a fashion of ranitidine, if the value of free drug is 3.5mcg/ml and the
similar to Enterohepatic recycling bound drug is 2.1mcg/ml?
5. What is the total drug plasma concentration and ἀ value
of ranitidine, if the value of free drug is 3.75 mcg/ml and
the bound drug is 3. 45 mcg/ml?
 42

7. If a dose of 1 g of a drug is administered IV to a patient

and the drug plasma concentration is determined to be
65mcg/ml, calculate the apparent volume of distribution.
8. A 50-kg woman was given a single IV dose of an
antibacterial drug at a dose level of 6 mg/kg. The Cp was
determined to be 8.4 mcg/mL. What is the Vd?

In pharmacokinetics and therapeutics, plasma or tissue samples are

often monitored to determine if a prescribe dose needs to be
adjusted.
 The pharmacist should be familiar with all units involving
dosing and be able to make conversions.
 Significant differences in plasma drug concentrations may
result if the dose is base on different methods.

Pharmacokinetic Parameters:
 Elimination rate constant – Fraction of vol. of distribution
that is cleared of drug during time interval.
 Biological Half life- Time required for the plasma con. to
be reduced to one half of the original value.
 Rate constant of absorption- constant time of the drug
being absorb in the body.
 Apparent volume of distributions
 Area under the curve
 Clearance- is the hypothetical Vd in ml of the
unmetabolized drug which is cleared per unit of time.
( ml/min, ) by any pathway of drug removal ( renal,
hepatic and other pathways of elimination.
 Renal Clearance- is the hypothetical plasma volume in ml
( Vd ) of the metabolized drug which is cleared in one
minute via kidney.
 Total clearance or Total Systemic clearance- clearance of
the hypothetical plasma volume in ml ( Vd ) of a drug per
Formula for volume of distribution or apparent volume of unit of time due to excretion via kidney, liver, lungs, & skin
distribution:
D
 Vd =
Cp
1. A patient received a single intravenous dose of 300mg of a
drug substance that produced an immediate blood
concentration of 8.2 mcg/ml. calculate the apparent
volume of distribution.
2. If a 6mg dose of a drug is administered iv and produces
blood concentration of 0.4mcg/ml calculate the apparent
volume of distribution?
3. A patient received an iv dose of 10mg of a drug. A blood
sample was drawn and it contained 40mcg/100ml.
Calculate the apparent volume of distribution for a drug.
4. Four hours following the iv administration of a drug, a
patient 70kg was found to have a drug blood level
concentration of 10 mcg/ml. assuming the apparent
volume of distribution is 10 % of body weight, calculate
the total amount of drug in the body fluids 4 hours after
the drug administered.
5. The volume of distribution for a drug was found to be 10
liters with a blood level concentration of 2mcg/ml.
Calculate the total amount of drug present in the patient.
6. The volume of distribution for chlordiazepoxide has been
determined to be 34 liters. Calculate the expected plasma
concentration of a drug in micrograms per deciliter,
immediately after an iv dose of 5mg.
 43

1. If the plasma concentration of viomycin after iv bolus

administration was found to be 10mcg/ml and 5.5mcg/ml
at 2 and 4 hours respectively. Assuming one compartment
model and first order reaction.

Calculate:
1. A drug suspension (125 mg/mL) decays by zero order
a) Elimination rate constant
kinetics with a reaction rate constant of 0.5 mg/mL/hr.
b) Half life
What is the concentration of intact drug remaining after 3
c) Concentration of drug at time zero(C = 1.26 mcg/ml )
days? How long will it take the drug to reach 90% of its
d) Vd, if dose administered was 300mg
original concentration?
e) Total Systemic clearance in (ml/min )
2. Cefalexin suspension (250mg/mL) deminished by zero
f) Renal clearance, Clr if fraction excretion unchanged in
order kinetics with a reaction rate constant of 0.65
urine is 0.8 .
mg/mL/hr. What is the concentration of cefalexin at 18 hr
time interval.
3. Paracetamol suspension (120mg/mL) deminished by zero
order kinetics with a reaction rate constant of 0.75
mg/mL/hr. What is the concentration of cefalexin at 12 hr
time interval.
 44

2. The equation that best fits the plasma concentration level

curve of oxacillin after an i.v. bolus dose of 2000mg
( assuming one compartment and first order kinetics ) .
Equation is 143mcg/mle−0.87 t

Calculate for:
a) Vd
1
b) Elimination t of the drug
2
c) Plasma concentation after 6 hours
d) Amount of drug that will left in the body after 6 hours
e) When should the next dose be administered if the drug
becomes ineffective when the plasma falls below
50mcg/ml.?
f) Therapeutic index of the oxacillin if the therapeutic range
is 50mcg/ml to 500mcg/ml.
g) How much dose should be administered to attain an 4. A dose of 325mg of a new drug is injected iv to a healthy
instantaneous plasma concentration of 500mcg/ml volunteer and the following blood data was obtained.
h) How long will the plasma level lie in the therapeutic Assume that the drug follows one copartment model and
window if the above dose and concentration is given As iv 1
calculate all possible parameters. KE, t , Co, Vd, ClT, and
bolus. 2,
AUC.
Slope: y2= 5.8mg/L, y1= 18.3 mg/L, x2= 6hrs, x1= 2 hrs
Co= 1.4955mg/L
Time Conc (mg/L)
(hrs)
2 18.3
4 10.1
6 5.6
8 3.3
10 1.8
12 1.0
16 0.31
20 0.21

5. Negamycin is a new antibiotic with an average dose 1.5

mg/kg and a half-life of 2 hours and
CP = 1.567mcg/ml. The weight of the patient 147lb. Compute for
the following.

a.) Dose,
b.) Vd,
c.) KE,
d.) ClT
e.) Renal Clearance F= 0.067, hepatic extraction rate if
blood flow to liver is 1.7L/min?
3. The half-life of propranolol in 60kg patient is 4hours and f.) If the blood flow rate to the liver reduces to 0.08L/min
Vd is 5.5 L/kg. in situations of CFF, what will be the new hepatic and Total
systemic clearance values?
Determine the following parameters? g.) What will be the percent decrease in overall clearance
a) Total Systemic Clearance of drug?
b) Renal clearance if the fraction unchanged in urine is
0.047. 6. A new drug with an average dose 1.5 mg/kg and a half-life
c) If the drug is eliminated only by hepatic and renal routes, of 3 hours and
What will be the hepatic extraction rate if blood flow to CP = 1.765mcg/ml. The weight of the patient 147lb. Compute for
liver is 1.5L/min? the following.
d) If the blood flow rate to the liver reduces to 0.08L/min in a.) Dose,
situations of CCF, what will be the new hepatic and Total b.) Vd,
systemic clearance values? c.) KE,
e) What will be the percent decrease in overall clearance of d.) ClT
drug? e.) Renal Clearance F= 0.077, hepatic extraction rate if
blood flow to liver is 1.8L/min?
 45

f.) If the blood flow rate to the liver reduces to 0.069L/min

in situations of CFF, what will be the new hepatic and Total
systemic clearance values? The plasma concentration after the 250 mg intravenous bolus dose
g.) What will be the percent decrease in overall clearance of an antibiotic is given below. Plot the data and describe the
of drug? pharmacokinetic model.

Calculate the following:

1. Elimination rate Constant
2. Half Life
3. Apparent volume of Distribution
4. AUC
5. Total Area under the Curve

Time Conc (mcg/ml)

(hrs)
1.0 8.0
2.0 6.3
3.0 4.9
4.0 4.0
5.0 3.2
6.0 2.5
7.0 1.9

The plasma concentration after the 350 mg intravenous bolus dose

of an vancomycin is given below. Plot the data and describe the
pharmacokinetic model.

Calculate the following:

1. If the plasma concentration of viomycin after iv bolus 1. Elimination rate Constant
administration was found to be 10mcg/ml and 5.5mcg/ml 2. Half Life
at 2 and 4 hours respectively. Assuming one compartment 3. Apparent volume of Distribution
model and first order reaction. 4. AUC.
Calculate: 5. Total area under the curve
1. Elimination rate constant
2. Half life Time Conc (mcg/ml)
3. Concentration of drug at time zero ( Co= 1.26 mcg/ml ) (hrs)
4. Vd, if dose administered was 300mg 1.5 7.0
5. Total Systemic clearance in (ml/min )
2.0 5.5
6. Renal clearance, Clr if fraction excretion unchanged in
3.0 4.5
urine is 0.8 in (ml/min)
4.0 4.0
5.0 3.5
6.0 2.5