Biopharmaceutics

ADME
Bio pharmaceutics is defined as study of factors influencing the rate and amount of drug that reaches the
systemic circulation and the use of this information to optimize the therapeutic efficacy of products.
Absorption: The process of movement of drug from its site of administration to systemic circulation.
Bioavailability:
Rate and extent (amount) of drug absorption.
Drug distribution: The movement of drug between one compartment and other (generally blood and
extracellular tissues).
Elimination:
The process that tends to remove the drug from the body and terminate its action.
Elimination occurs by two processes;

Biotransformation Excretion
--- It usually inactivates the drug - which leads to exit of drug from the body.
Pharmacokinetics:
 Study of time course of drug ADME and their relationship with its therapeutic and toxic effects of
drug.
 It is related with ADME of drug and its relationship with dose, dosage form, dosing frequency and
route of administration.
 Thus it is considered to be the study of what body does to the drug.
Pharmacodynamics:
 It is concerned with biochemical and physiological effects of drug and its mechanism of action.
 It is related to concentration of drug in the body at the site of action and its relation to the effect
observed.
 Thus it is considered to be the study of what drug does to the body.
Drug absorption:
 Process of movement of unchanged drug from site of administration to systemic circulation.
 Effectiveness of drug can be assessed by its concentration at the site of action however, it is difficult to
measure drug concentration at such a site, thus conc. of drug can be measured more accurately in
plasma.
 First Pass metabolism- metabolism of drug at specific location in the body which leads to reduced
drug concentration of active drug.
Drugs that have to enter the systemic circulation to exert their effect can be administered by three
major routes;
The enteral route: includes gastrointestinal, sublingual/buccal and rectal routes. GI route is most
common for administration of majority of drugs.
The parenteral route:
Includes all routes of administration under one or more layers of skin.
The topical route:
Includes skin, eyes or other specific membranes.
Gastrointestinal absorption of drugs:
The oral route of drug administration is the most common for systemically acting drugs and thus GI
absorption is mostly consider.
Cell membrane: structure and physiology:
 For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it
must pass through one or more biological membranes or barriers at various locations.
 Such a movement of drug across the membrane is called as drug transport.
Basic structure of cell membrane:

 It consists of double layer of amphiphillic phospholipid molecules with nonpolar tail orients inward to
form hydrophobic phase.
 Polar heads oriented outwards to form outer hydrophilic boundaries.
 Globular protein molecules are associated on either side of these hydrophilic boundaries and also
interspersed within the membrane structure.
 In short, membrane is a mayonnaise sandwich where a biomolecular layer of lipids is contained
between two parallel monomolecular layers of protein.
 The hydrophobic core of the membrane is responsible for relative impermeability of the polar
molecules.
 Aqueous filled pores of 4 to 10A0, in diameter are also present in the membrane structure through
which inorganic ions and small organic water soluble molecules like urea can pass.
 The GI lining barriers allows most nutrients like glucose, amino acids, fatty acids, vitamins etc. to
pass rapidly through it into the systemic circulation.
Mechanisms of drug absorption:
1. Transcellular/intracellular transport
2. Paracellular/intercellular transport
3. Vesicular transport
A. Transcellular transport:
 Is defined as passage of drug across GI epithelium.
 Is most common pathway for drug transport.
It involves three steps;
 Permeation of GI epithelial cell membrane.
 Movement across intracellular space.
 Permeation of the lateral or basolateral membrane.
a) Passive transport Processes:
 These transport processes do not require energy other than that of molecular motion (Brownian
motion) to pass through the lipid bilayer.
It an be further classified into;
 Passive diffusion
 Pore transport
 Ion pair transport
 Facilitated diffusion
b) Active transport Process:
 These transport process require energy from ATP to move drug molecules from extracellular to
intracellular environment.
They are of two types;
 Primary active transport
 Secondary active transport
B. Paracellular transport:
Is defined as the transport of drug through the junctions between the GI epithelial cells. This pathway is of
minor importance in drug absorption.
C. Vesicular transport (Endocytosis):
Like active transport these are also energy dependent processes but involve transport of substances within
vesicles into a cell.
Classified into
 Pinocytosis
 Phagocytosis
Passive diffusion:
 Also called non-ionic diffusion, it is the major process for absorption of more than 90% of drugs.
 The driving force for this process is concentration gradient, which is defined a difference in drug
concentration on either side of the membrane.
 During passive diffusion drug present in the aqueous solution at the absorption site partitions and
dissolves in the lipid material of the membrane and finally leaves it by dissolving again in an aqueous
medium, inside of the membrane.
 It is expressed by Ficks first law of diffusion; which states that the drug molecules diffuse from a region
of higher concentration to one of the lower concentration until a equilibrium is achieved.
 The rate of diffusion is directly proportional to concentration gradient across the membrane.
dQ/dt = DAKm/w (CGIT-C)
h
Where,
dQ/dt = rate of drug diffusion.
D = diffusion coefficient of drug through the membrane.
Km/w= Partition coefficient of drug between lipoidal membrane and aqueous GI fluids.
(CGIT-C) = difference in concentration of drug in the GI fluid and the plasma.
h = thickness of membrane.
Characteristics of passive diffusion
 Drug moves down the conc. gradient.
 The process is energy independent.
 The rate of drug transfer is directly proportional to concentration gradient.
 Greater the membrane/water partition coefficient of drug, faster the absorption.
 As membrane is lipoidal, a lipophilic drug diffuse at faster rate.
 Initially when the drug is ingested, CGIT>>>C and a large concentration gradient exists thereby
acting as the driving force for absorption.
 Once, the passively absorbed drug enters the blood, it is rapidly swept away and distributed into a
much larger volume of body fluid and hence, the concentration of drug at the absorption site, C GIT, is
maintained greater than the concentration of drug in plasma.
 Such a condition is called as sink condition for drug absorption.
 Under usual conditions of absorption, D, A, Km/w and h are constants, the term DAK m/w/h can be
replaced by permeability coefficient P.
 Due to sing condition C is small as compared to C GIT, thus equation becomes;

dQ/dt = PCGIT
Pore transport
 Also called as convective transport, bulk flow or filtration.
 This mechanism is responsible for transport of molecules into the cell through the protein channels or
present in the cell membrane.
 The driving force is the osmotic pressure difference across the membrane.
 This process is imp for absorption of low molecular weight and low molecular size and water soluble
molecules. Eg: Water, glucose.
Ion-pair transport:
 Drugs like quaternary ammonium compounds which ionize at all pH conditions are absorbed by ion
pair transport.
 They penetrate the membrane by forming reversible neutral complexes with endogenous ions of GIT
like mucin.
 Thus, this complexes have both the required lipophilicity and aqueous solubility for diffusion.
 Such phenomenon is called as ion pair transport. Eg: Propranolol forms pair with oleic acid and
absorbed by this mech.
Carrier mediated transport:
 Some polar drug cross the membrane and will be absorbed with the help of specialized transport
mechanism like carriers that binds reversibly or non-covalently with the solute molecules to be
transported.
 This carrier solute complex traverses across the membrane and dissociates and discharge the solute
molecule.
 The carrier return to its original site to complete the cycles by accepting fresh solute molecule.
 Eg. of carriers are proteins, enzymes
 The carrier proteins always has an nonpolar outer surface which allows it to be soluble within the
liquid of the membrane.
 The carriers have no directionality, they work with same efficiency in both the directions.
 The carriers have special affinity for essential nutrients.
 As the number of carrier is limited, the transport system is subjected to competition between agents
having similar structure.
Two types of carrier mediated systems;
 Facilitated diffusion
 Active transport
Facilitated diffusion:
 It is a carrier mediated transport system that operates down the concentration gradient (downhill
transport).
 The driving force is concentration gradient, hence it is a passive process.
 No energy expenditure is involved.
 Eg: vitamin B12, forms a complex with intrinsic factor and then transported across intestinal
membrane by carrier system.
Active transport:
This transport mechanism require energy in the form of ATP.
Two types;
 Primary active transport
 Secondary active transport
Primary active transport:
 There is direct ATP requirement.
 The process transfers only one ion or molecule in only one direction and thus known as uniporter.
 Eg: absorption of glucose.
Carrier proteins involved in active transport are;
a) Ion transporter: are responsible for transporting ions in or out of cells.
 A classic example of ATP driven ion pump is proton pump.
Two types of transporter
Organic anion transporter: involved in absorption of atorvastatin
Organic cation transporter: involved in absorption of diphenhydramine.
b) ABC transporter:
 Are responsible for transport of small foreign molecules out of cells.
 Example is P-glycoprotein, which pumps hydrophobic drugs out of cells.
Secondary active transport:
 There is no direct requirement of energy.
 The process transport another ion or molecules in same or in opposite direction.
 Thus it is further divided into;
Symport (co-transport): involves movement of both the molecules in the same direction.
Eg: Na+ glucose symporter.
Antiport (Counter transport): Involves movement of molecules in opposite direction.

Active transport differs from facilitated diffusion in;

 The drug is transported from a region of lower to higher concentration (Uphill process).
 The process is faster than passive diffusion.
 As the process needs energy, it can be inhibited by metabolic poisons that interfere with energy
production like, fluorides and cyanides.
Endocytosis:
 Is a minor transport mechanism which involves engulfing extracellular material within a segment of
the cell membrane to form a vesicles which is then pinched off intracellularly.
 This phenomenon is responsible for the cellular uptake of macromolecular nutrients like fats and
starch, oil soluble vitamins and water soluble vitamins.

It includes two types of processes;

Phagocytosis (Cell eating): adsorptive uptake of solid particulates.
Pinocytosis (Cell drinking): uptake of fluid solute.
Phagocytosis:
Pinocytosis:
This process is important in absorption of oil soluble vitamins and in uptake of nutrients.
Factors influencing drug absorption and bioavailability:
Physicochemical properties of drug substance:
1. Drug solubility and dissolution rate:
 The two critical slower rate determining processes in the absorption of orally administered drugs
are;
 Rate of dissolution and
 Rate of drug permeation through biomembrane.
 Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs like greseofulvin.
 Absorption of such drugs is dissolution rate limited.
 If the drug is hydrophilic then dissolution is rapid and RDS in the absorption of such a drug is rate
of permeation through the biomembrane.
 Thus absorption of such a drug is permeation rate limited.
Based on solubility and intestinal permeability of drugs, BCS classification system was developed.

Class Solubility Permeability

I High high
II low High
III High Low
IV Low Low

Class I drugs are well absorbed orally since they have no solubility and permeability limitation.
Class II drugs shows variable absorption owing to solubility limitation.
Class III drugs also show varying absorption owing to permeability limitation.
Class IV drugs are poorly absorbed due to both solubility and permeability limitation.
Theories of drug dissolution:
Dissolution is a process in which a solid substance solubilize in a given solvent i.e. mass transfer from the solid surface to the liquid
phase.
Several theories of drug dissolution are;
 Diffusion layer theory
 Dankwerts model/ penetration or surface renewal theory
 Interfacial barrier model/ double barrier or limited solvation theory
Diffusion layer theory:
 This is the simplest and most common theory for dissolution.
It consists of two steps;
 Solution of the solid to form a thin film or layer at the solid/liquid interface called as stagnant film or diffusion layer which is
saturated with the drug. This step is rapid.
 Diffusion of soluble solute from the stagnant layer to the bulk of solution. This step is slower and thus is rate determining step in
the drug dissolution.
Noys and Whiteny gives the equation to study rate of dissolution
dC/dt = k (Cs-Cb)
Where, dC/dt = dissolution rate of the drug
K = dissolution rate constant.
Cs = conc. Of drug in stagnant layer.
Cb = Conc. Of drug in bulk
This equation was based on Ficks first law of diffusion.
Nernst and Brunner incorporated Ficks first law of diffusion and modified the Noyes- Whitney equation to
Danckwert’s Model (Surface renewal theory):
 Dankwerts did not approve of the existence of a stagnant layer and suggested that turbulence in the
dissolution medium exists at the solid/ liquid interface.
 As a result, the agitated fluid consisting of macroscopic mass of eddies or packets reach the
solid/liquid interface in random fashion due to eddy current, absorb the solute by diffusion and carry
it to bulk of solution.
 Such solute containing packets are continuously replaced with new packets of fresh solvent, due to
which drug concentration at solid/liquid interface never reaches Cs and has a lower limiting value of
Ci.
 Since the solvent packets are exposed to new solid surface each time the theory is called as surface
renewal theory.
Interfacial barrier theory(limited solvation theory):
 The diffusion layer model and Dankwerts model were based n two assumption;
 The rate determining step that controls dissolution is the mass transport.
 Solid-solution equilibrium is achieved at the solid/liquid interface.
 According to interfacial barrier model, an intermediate concentration can exist at the interface as a
result of solvation mechanism and is a function of solubility rather than diffusion.
 When considering the dissolution of crystal, each face of crystal will have a different interfacial
barrier.
Such a concept is given by;
G = Ki (Cs-Cb)
Where;
G = dissolution rate per unit area and
Ki = effective interfacial transport constant.
2. Particle size and effective surface area of the drug:
 PS and SA of solid drugs are inversely proportional to each other.
 Smaller the drug particle, greater the surface area, thus increases dissolution rate.
 The effective surface area (which is area of solid surface exposed to the dissolution medium) is
proportional to dissolution rate.
 Decrease in particle size can be achieved by micronization, which increases solubility, thus faster
dissolution.
3. Polymorphism and Amorphism:
 Depending upon the internal structure, a solid can exist either in crystalline or amorphous form.
When a substance exists in more than one crystalline form, the different forms are known as polymorphs.
Types of polymorphs:
Enantiotropic polymorphs:
Is the one which can be reversibly changed into another form by altering the temperature or pressure eg:
Sulphur.
Monotropic polymorphs:
Is the one which is unstable at all temperature and pressures.
Stable and metastable forms.
Amorphous > Metastable > stable.
4. Hydrates/Solvates:
 The crystalline form of a drug can either be a polymorph or a molecular drug or both.
 The stoichiometric type of adducts where the solvent molecule are incorporated in the crystal lattice of
the solid is called as solvates and the trapped solvent is called as solvent of crystallization.
 The solvates can exists in different crystalline forms called as pseudopolymorphs.
 When the solvent in association with the drug is water, the solvate is known as a hydrate.
 Generally, the anhydrous form of a drug has greater aqueous solubility than the hydrates, b’coz the
hydrates are already in interaction with water and thus have less energy for crystal breakup compared
to anhydrates.
5. Salt form of drug:
 Easiest approach to enhance the solubility and dissolution rate of weak acids or weak bases is to
convert them into their salt form.
 Generally, with weakly acidic drug, a strong base salt is prepared such as sodium and potassium salts
of barbiturates and sulphonamides.
 In case of weakly basic drugs, strong acid salt is prepared like hydrochloride or sulphate salts of
several alkaloidal drugs.
 The solubility of salts of weak acid is enhanced by precipitation of drug as very fine particles.
Drug pKa and lipophilicity and GI pH-pH partition hypothesis:
 The pH partition theory explains in simple terms, the process of drug absorption from GIT and its
distribution across all biological membranes.
 The theory states that for drug compounds of molecular weight greater than 100, which are primarily
transported across the membrane by passive diffusion, the process of absorption is governed by;
 The dissociation constant (pKa) of the drug.
 The lipid solubility of unionized drug
 The pH at the absorption site.
Lipophilicity and drug absorption:
 As mentioned earlier, it is the pKa of a drug that determines the degree of ionization at a particular
pH and only if the unionized drug is sufficiently lipid soluble, it is absorbed into the systemic
circulation.
 Thus, even if the drug exist in the unionized form, it will be poorly absorbed if it has poor lipid
solubility or (low Ko/w).
Ideally for absorption;
 Drug should have sufficient aqueous solubility in fluid at absorption site
 Lipid solubility to facilitate partitioning of drug in lipoidal membrane.
 Perfect HLB should be there for optimum bioavailability
Drug permeability and absorption:
Most orally administer drugs enter the systemic circulation by passive diffusion and their absorption is
expressed by
M = Peff A Capp tres
Peff = effective membrane permeability
A= surface area available for absorption
Capp = apparent luminal drug concentration.
Tres = residence time of drug in GI lumen.
 Since it is difficult to alter or control the surface area and residence time of drug, thus for improving
absorption, permeability or concentration needs to be enhanced.
 The three major characteristics that determine the passive transport or permeability of drug across
intestinal epithelium are;
 Lipophilicity of drug i.e. log P.
 Polarity of drug which is measured by number of H-bond acceptor and number of H-bond donors on drug
molecule.
 Molecular size.
The net effect of all these properties on its intestinal permeability is expressed by Lipinski rule of five.
 Molecular weight of drug: ≤ 500
 Lipophilicity of drug, log P: ≤ 5
 Number of H bond acceptor: ≤ 10
 Number of H bond donor ≤ 5.
Drug stability:
 A drug for oral administration may destabilize either during its shelf life or in the GIT.
 Two problems resulting in poor BA of orally used drugs are;
 Degradation of the drug into inactive form, and
 Interaction with one or more different components either of the dosage form or those present in GIT to
Dosage form factors:
Disintegration time:
 DT is important in case of solid dosage forms like tablets and capsules.
 In vitro disintegration test is by no means if the disintegrated particles does not dissolve, absorption is not
possible.
 Sugar coated tablet have long DT.
 DT of a tablet related to binder present and compression force.
 A harder tablet with large amount of binder has long DT.
 After disintegration of a solid dosage form into granules, the granules must deaggregate into fine particles,
as dissolution is faster from fine particles.
Manufacturing/ processing variables:
 Drug dissolution is most imp in absorption of drug from conventional dosage forms.
 The dosage form related factors affects the dissolution and absorption of drug includes;
Excipients:
 Excipients are added to ensure acceptability, physicochemical stability during shelf life, optimum
bioavailability and functionality of drug product.
 More the number of excipients, more complex it is and greater the potential for absorption and
bioavailability problems.
 Commonly used excipients are lubricants, binders, granulating agents, Disintegrants etc.
1. Vehicles:
 Two types aqueous and Nonaqueous.
 Aqueous are soluble with biological fluid and thus drugs from them are rapidly absorbed.
 Solubilizes such as polysorbate 80 are sometimes used to promote solubility of drug in aqueous
vehicles.
2. Diluents:
 Are filler added when the dose is inadequate to produce necessary bulk.
 MCC, lactose are organic hydrophilic powders used in enhancing dissolution rate.
3. Binders and granulating agents:
 Used to hold powders together to form granules.
 Eg includes starch, cellulose derivatives, acacia, PVP.
 Like diluents hydrophilic binders show better dissolution with poorly wettable drugs.
 Non aqueous binder like EC retard the drug dissolution.
4. Disintegrants:
 These agents break the tablets on contact with water.
 Microcrystalline cellulose is good disintegrant but at high compression force, it may retard drug
dissolution.
5. Lubricants:
 To increase the flow of granules, to reduce interparticle friction, sticking or adhesion of particles to
dies and punches.
 Commonly used lubricants are hydrophobic in nature and inhibit wettability, thus disintegration and
dissolution.
 Best alternative is to uses SLS as it is soluble lubricant.
6. Surfactants:
 Are used as wetting agents, solubilizes, emulsifiers etc.
They increase absorption by;
 Promoting wetting of drugs
 Enhanced membrane permeability of drug.
7. Complexing agent:
 The complexation has been used to enhance the absorption of drug and bioavailability includes;
 Enhanced dissolution through formation of a soluble complex.
 Enhanced lipophilicity for better membrane permeability Eg: caffeine PABA complex.
Nature and type of dosage form:
 BA of drug depends upon nature and type of dosage form.
BA decreases in order
Solution > emulsion > suspension > capsules > tablets > coated tablet > enteric coated tablets >
sustained release products
Product age and storage conditions:
 A number of changes occur in dosage form due to alteration in storage condition which affects the
BA of drug.
 Eg: With solution dosage form, precipitation of drug due to altered solubility, i.e due to conversion of
metastable into poorly soluble form occur during shelf life of drug.
 Changes in particle size distribution observed with number of suspension dosage forms.
Patient related factors:
Age:
 In infants, the gastric pH is high and intestinal surface and blood flow to GIT is low resulting in
alerted absorption pattern in comparison to adults.
 In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased
intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial overgrowth in
small intestine.
Gastric emptying:
 Apart from dissolution and permeation of drug, the passage from stomach to the small intestine, called
as gastric emptying can be a rate limiting step in drug absorption as major site of absorption is small
intestine.
 Thus, generally rapid gastric emptying increases BA of drug.
Rapid gastric emptying is advisable; where;
 A rapid onset of action is desired eg: sedative
 Dissolution of drug occurs in the intestine eg: enteric coated dosage forms.
 Drugs are not stable in the gastric fluid.
 For better dissolution and absorption, the gastric emptying can be promoted by taking the drug on
empty stomach.
Several factors are used to quantify gastric emptying;
Gastric emptying rate:
Is the speed at which the stomach contents empty into the intestine.
Gastric emptying time:
 Is the time required for the gastric contents to empty into small intestine. Longer the gastric emptying
time, lesser the gastric emptying rate.
 A large number of factors influence gastric emptying as below;
Volume of meal: larger the bulk of meals, longer the gastric emptying time.
Physical state and viscosity of meal: liquid meals take less than an hour to empty whereas a solid meal
may take as long as 6 to 7hrs.
GI pH: Gastric emptying is retarded at low stomach pH and promoted at higher or alkaline pH.
Intestinal transit:
 Since small intestine is the major site for absorption of most drugs, long intestinal transit time is
desirable for complete drug absorption.
Delayed intestinal transit is desirable for;
 Drugs that dissolve or release slowly from their dosage forms.
 Drugs that dissolve only in the intestine,.
 Drugs which are absorbed from specific sites in the intestine.
 Drugs like metoclopramide that promotes gastric emptying and intestinal transit enhance absorption
of rapidly soluble drugs.
Gastrointestinal pH:
 A 107 fold difference in the hydrogen ion concentration is observed between the gastric and colon
fluids.
 The GI pH generally increases gradually as one move down the stomach to the colon
 GI fluid pH influence drug absorption in several ways;
Disintegration:
 Disintegration of some dosage form is pH sensitive.
 With enteric coated formulations, the coat dissolves only in intestine followed by disintegration of
tablet.
Dissolution:
 A pH that favors formation of salt of drug enhances the dissolution of that drug.
 Weakly acidic drug dissolves rapidly in the alkaline pH of the intestine whereas basic drugs dissolves
in acidic pH of the stomach.
Absorption:
 Depending upon the drug pKa and whether its an acidic or a basic drug, the GI pH influences drug
absorption by determining the amount of drug that would exist in the unionized form at the site of
absorption.
Stability:
 GI pH also influences the stability of drugs.
 The acidic stomach pH is known to affect degradation of penicillin G and erythromycin.
 This can be overcome by preparing prodrugs of such drugs that do not degrade.
Disease states:
Several disease states can influence the rate and extent of drug absorption.
These includes;
Gastrointestinal diseases: namely;
Altered GI motility
Gastrointestinal diseases and infection:
 The celiac disease and Crohn’s disease.
 Abnormalities associated with celiac disease include increased gastric emptying rate and GI
permeability, altered intestinal drug metabolism, all of which impair drug absorption.
 Conditions associated with Crohn’s disease that can alter absorption pattern are altered gut wall
microbial flora, decreased gut surface area, and intestinal transit time.
Cardiovascular diseases:
Several changes associated with congestive cardiac failure influence bioavailability of a drug viz;
decreased blood flow to GIT and altered GI pH.
Hepatic diseases:
Disorders such as hepatic cirrhosis influence BA mainly of drugs undergoing first pass metabolism eg:
Proranolol.
Blood flow to GIT:
 The GIT is extensively supplied by blood capillary network and the lymphatic system.
 Since the blood flow rate to GIT is 500 to 1000 times more than the lymph flow, most drugs reach the
systemic circulation via blood whereas only a few drugs, especially lipid soluble are removed by
lymphatic system.
 For the drugs with high permeation rates i.e. lipid soluble drugs, the GI perfusion rate could be a rate
limiting step in the absorption.
 Food influence blood flow to GIT. The perfusion rate increases after meals but drug absorption is not
influenced significantly.
Gastrointestinal contents:
a. Food drug Interaction: presence of food may either delay, reduce, increase or may not affect drug
absorption.
 As a general rule, drugs are better absorbed under fasting conditions and presence of food retards it.
Decreased drug absorption by the food could be due to;
 Formation of poorly soluble or unabsorbable complex.
 Increased viscosity due to food thus preventing drug dissolution.
Increased drug absorption following a meal could be due to;
 Increased time for dissolution of a poorly soluble drug.
 Enhanced solubility due to GI secretions like bile.
b. Fluid volume: administration of drug with large fluid volume results in better dissolution and
enhanced absorption.
c. Interaction of drug with normal GI constituents: the GIT contains mucin, bile salts and enzyme
which influence drug absorption.
 Mucin, a protective mucopolysaccharide that lines the GI mucosa, interacts with streptomycin and
retards their absorption.
d. Drug drug interaction in the GIT:
 Antidiarrheal preparations retards the absorption of coadministered drugs like lincomycin.
 Antacid retards absorption of tetracycline.
Contact time with gastrointestinal mucosa:
 If a drug moves through GI tract very quickly, as in severe diarrhea, it is not well absorbed.
 This is because of reduced drug to GI mucosa contact time.
First pass metabolism:
For orally administered drug, the main reasons for its decreased BA are;
 Decreased absorption
 Destruction of drug
 First pass metabolism.
 Before a drug reaches blood circulation, it has to pass through GIT and the liver.
 The loss of drug through metabolism by such organs during its passage to systemic circulation is
called first pass metabolism.
 The diminished drug concentration or complete absence of the drug in plasma after oral
administration is indicative of first pass effect.
The systems which affect the presystemic metabolism of drugs are;
 Luminal enzyme which include digestive enzyme.
 Gut wall enzyme
 Hepatic enzymes.
 Distribution of drugs:
 After entry into systemic circulation, the drug is subjected to number of processes called as
disposition processes.
 Disposition is defined as the process that tend to lower the plasma concentration of drug.
 Two major drug disposition processes are;
Distribution: reversible transfer of drug between compartments.
Elimination: which causes irreversible loss of drug from the body.
Thus,
 Distribution is defined as the reversible transfer of drug between one compartment and another.
 One compartment is always blood and other is extravascular fluids and tissues. Thus distribution is
reversible transfer of drug between the blood and extravascular tissue.
Steps in distribution:
Factors affecting distribution of drugs:
Degree of ionization (pKa):
o/w permeability:
Physiological barriers to distribution of drugs:
 A barriers can be a permeability restriction to distribution of drugs to some tissues.
Some of the imp barriers are
1. The simple capillary endothelial barrier:
 The membrane of capillaries that supply blood to most tissues is, not a barrier to drugs.
 Thus, all drugs ionized or unionized, with a molecular size less than 600 Daltons, diffuse through the
capillary endothelium into the interstitial fluid.
 Only drugs bound to the blood components are restricted because of the large molecular size of the
complex.
2. The simple cell membrane barrier:
 Once a drug diffuse from the capillary wall into the extracellular fluid, its further entry into cells of
most tissues is limited by its permeability through the membrane.
 Such simple cell membrane is similar to the lipoidal membrane in the GI absorption of drugs.
 The physicochemical properties that influence permeation of drugs across such a barrier are
summarized in figure.
3. Blood brain barrier (BBB):
 Unlike the capillaries found in other parts of body, capillaries in brain are specialized and less
permeable to water soluble drugs.
 The brain capillaries consists of endothelial cells which are joined to one another by tight
intercellular junction, what is called as BBB.
 The special cells, pericytes and astrocytes, found at the base of the endothelial membrane, forms a
solid envelope around the brain capillaries.
 Thus, the intercellular passage (between cells) of drug is blocked and for a drug to enter into a brain,
it has to pass through the cells. (transcellular pathway).
 However, Intranasally administered drug directly enters into Brain due to connection between
submucosal area of nose and olfactory lobe of the brain.
Thus solute enter into the brain via;
 Passive diffusion through lipoidal barrier which is applicable to small molecule having high o/w
partition coefficient.
 Active transport of essential nutrients such as sugar and amino acids.
Different approaches to cross BBB:
4. Blood cerebrospinal fluid barrier:
 The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus of the lateral. Third and fourth
ventricles and is similar in composition to the ECF of brain.
 The capillary endothelium that lines the choroid plexus have open junctions and drugs can flow freely
into the extracellular space between the capillary wall and the choroidal cells.
 However, the choroidal cells are joined to each other by tight junctions forming the blood-CSF barrier
which has permeability characteristics similar to BBB.
 Same with BBB, lipophilic drug can cross.
5. Blood placental barrier:
 The maternal and foetal blood vessels are separated by a number of tissue layers made of foetal
trophoblast basement membrane and the endothelium which together constitutes placental barrier.
 The thickness of this barrier is 25 micron in early pregnancy that reduces to 2 microns in full term.
 Drugs with mol. Weight less than 1000 Daltons and moderate to high lipid solubility can cross by
simple diffusion.
 Nutrients essential for foetal growth are transported by carrier mediated process.
6. Blood testis barrier:
 This barrier is located not at the capillary endothelium but at sertoli-sertoli cell junction.
 It is the tight junctions between the neighbouring sertoli cells that act as the blood-testis barrier.
 This barrier restricts the passage of drug to spermatocytes and spermatids.
Organ/Tissue size and perfusion rate:
Perfusion rate: the volume of blood that flows per unit time per unit volume of the tissue.
 It is expressed as ml/min.ml of the tissue.
 Distribution will be perfusion rate limited when;
 The drug is highly lipophilic.
 The membrane across which drug is supposed to diffuse is highly permeable.
 Greater the blood flow, faster the distribution
Table shows various tissues with their perfusion rate which indicates the rapidity, with which the drug
will be distributed to tissues.
 The extent to which drug is distributed in a particular tissue or organ depends upon the size of the
tissue and the tissue/blood partition coefficient of the drug.
Eg: Thiopental.
 This lipophilic drug has high tissue/blood partition coefficient towards the brain and adipose tissue.
 As brain is highly perfused organ, thiopental rapidly diffuses into the brain with rapid onset of action.
Binding of drug to tissue components:
 A drug in body can bind to several components such as the plasma proteins, blood cells and
haemoglobin and extravascular proteins and other tissues.
Miscellaneous factors affecting distribution:
Age:
 Differences in distribution pattern of a drug in different age groups are mainly due to difference in;
 Total body water: is much greater in infants.
 Fat content: higher in infants and elderly.
 Skeletal muscles: are in infants and in elderly.
 Organ composition: The BBB is poorly developed in infants, hence grater penetration of drug in the
brain.
 Plasma protein content: low albumin content in both infants and in elderly.
Pregnancy:
 During pregnancy, the growth of uterus, placenta and foetus increases the volume available for
distribution.
Obesity:
 In obese persons, the high adipose tissue content can take up large fraction of lipophilic drugs.
Disease states:
 A number of mechanisms may be involved in the alteration of drug distribution in diseases states;
 Altered albumin and other drug-binding protein characteristics.
 Altered perfusion to organs.
 Altered tissue pH.
Drug interactions:
Drug interactions that affect distribution are mainly due to differences in plasma protein or tissue
binding of drugs.
Volume of distribution:
 A drug in circulation distributes to various organs and tissues.
 When the process of distribution is completes, different organs and tissues contain varying
concentration of drug which can be determined by volume of tissue in which drug is present.
 As diff. tissue have diff conc. Of drug, the volume of distribution cannot have a true physiological
meaning.
 There exist a relationship between concentration of drug in plasma C, and the amount of drug in the
body X.
XαC
X = Vd C
Where,
Vd = proportionality constant having the unit of volume and is called as apparent volume of distribution.
 It is defined as, the hypothetical volume of body fluid into which a drug is dissolved or distributed.
 It is called as apparent volume because all parts of the body equilibrated with the drug do not have
equal concentration.
Thus Vd is given by the ratio
Apparent volume of distribution = Amount of drug in body/Plasma drug concentration

Vd = X/C
The real volume of distribution has direct physiological meaning and is related to the body water.

Methods of studying drug distribution:

Microdialysis:
 This involves insertion of very fine probes into tissues of the living body, mostly into fluid spaces,
such as the CSF.
 The probes consists of two concentric tubes and a semipermeable membrane separating them,
positioned such that an artificial dialysis fluid can slowly infused through the probe and pass the
membrane.
 Unbound drug molecules in the tissue surrounding the probe diffuse into the dialysate which is then
collected for analysis.
 Invasive method.
 Matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI):
 It is used to study the drug localization within micro environmental tissue compartment.
 This sections of animal tissue are exposed to pharmaceutical drugs by either spotting or submerging.
 MALDI-MS is then performed on the tissue to localize drug distribution pattern.
Autoradiography:
 Radioactively labeled drug substance under investigation is administered to test animals and are
killed and frozen sections of tissues are prepared.
 An image of the radiation is obtained by placing the section next to a photographic emulsion.
 Thus if a whole body section is used, and the radioactivity is specifically localized in highly perfused
organs, such as lungs, the image reveal this.
 Comparison with a normal photograph is used to quantify the relative amount of radioactivity.
 This technique showed highly specific localization of drug in tissues.
Positron emission tomography:
 Synthetic radioactive isotopes (Eg: 11C, 13N) with half life values of 2-110 minutes and emits
positrons that interact with electrons to emit gamma radiation that can be detected outside the body.
 The isotopes are incorporated into drug molecules before the administration.
 PET scanning permits the production of images of live organism including humans.