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LECTURE 9
BIOPHARMACEUTICS &
PHARMACOKINETICS
PT606
By:
Nehal Emam, PhD.
Lecturer.
Pharmaceutics Department,
Sinai University, Kantara, Egypt.
Kinetics of Elimination
 Clearance (CL)
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❑ The pharmacokinetic parameter which gives a quantitative measuremet

of drug elimination.
❑ Clearance of a drug: The theoretical volume of plasma from which
the drug is completely removed in unit time (ml/min)
CL = Dose CL = Rate of elimination (K)
AUC Plasma concentration

 Fraction of apparent volume of distribution (avd) of drug from

which the drug is removed in unit time
 Clearance can be described in terms of eliminating organs
 CL(total) = CL (renal) + CL (hepatic) + Cl (other)

 CLtotal = k * vd
 Half life (t1/2)
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 Half-life = time required for serum plasma concentrations to

decrease by one-half (50%)
Formula:
k: elimination rate constant of
t1/2 = 0.693 the drug (fraction removed
per unit time)
k 0.693: natural log of 2

K= CL
Vd
➢ First order kinetics …… t1/2 is constant
➢ Zero order kinetics …… t1/2 increases with higher dose

If the dose is increased → clearance (CL)

t = 0.693× Vd
1/2
decreases → T1/2 increases → *chance of toxicity CL
# Key points to remember
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Elimination and Clearance are NOT the same thing.

 Elimination describes the rate of loss (mg/h, amount / time).

 While Clearance is a Pharmacokinetic parameter that measures the efficiency of drug

removal from the bloodstream within a specific time “Volume of plasma cleared of
drug/time”

It is calculated as the rate at which a drug is eliminated from plasma divided by the
plasma concentration of the drug (L/h, volume / time).

 Clearance = Rate of loss / Plasma Concentration of Drug

 Rate of Elimination = Plasma Concentration * Clearance

 If clearance is constant then the elimination of a drug will be linearly

proportional to the drug concentration.
 Kinetics of Drug Elimination
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a. First Order Kinetics

b. Zero Order kinetics

Note:
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50%

50%

✓ Constant fraction (%) ✓ Constant amount

✓ ↑ dose → ↑ rate of elimination ✓ ↑ dose → Constant elimination and may decrease
(Saturation)
✓ Constant Clearance ✓ Inconstant Clearance
✓ Fixed half life ✓ Changeable half life
✓ ↑ dose → No effect on half life ✓ ↑ dose → ↑ half life and toxicity occurs
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First Order Kinetics (Linear)
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✓ Constant fraction (%) of drug is eliminated at a constant

interval of time.

✓ Most of drugs follow first order kinetics

❑ 100ug/ml 50% 50ug/ml 50% 25ug/ml

2hr 2hr

And so on
First Order Kinetics (Cont…)
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✓ Rate of elimination is directly proportional to drug

concentration.
50% 50% 50%
❑ 200ug/ml 100ug/ml 50ug/ml and so on
2hr 2hr 2hr

Clearance remain constant

✓ The elimination processes are not saturated and can
adapt to the needs of the body, to reduce accumulation of
the drug
First Order Kinetics (Cont…)
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❑ t1/2 of drug would always remain constant

irrespective of the dose
First Order Kinetics (Cont…)
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First-order kinetics (linear y-axis) First-order kinetics (log y-axis)

▪ Plasma concentration is plotted against time , the resultant “ plasma

fall-out curve” → curvilinear.

▪ Log of plasma concentration are plotted against time , the resultant

curve → linear.
First Order Kinetics (Cont…)
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❑ After a single dose, about 97% of the drug

gets eliminated five t1/2 interval.
50% 50% 50%
100µg/ml 50µg/ml 25µg/ml
1t1/2 2t1/2 3t1/2
50% 50%
3.125µg/ml 6.25µg/ml 12.5µg/ml

5t1/2 4t1/2

***Complete drug elimination can occur after 5

half lives.
Zero Order Kinetics (Nonlinear)
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 Constant or Fixed amount of drug is eliminated per unit time.

✓ Rate of elimination remain constant irrespective of drug
concentration.

✓ Only few drugs follow zero order kinetics (at high doses)
✓ Ethyl alcohol exhibit zero order at virtually all plasma
concentrations.

✓ Also called capacity limited elimination

30ug/ml 30ug/ml 30ug/ml

• 100ug/ml 70 ug/ml 40 ug/ml 10 ug/ml
2hr 2hr 2hr Nil
Zero Order Kinetics (Cont…)
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 The rate of elimination is independent of the concentration of

the drug in the plasma. So increasing the dose does not result in
a proportionate rise in the extent of elimination.
30ug/ml 30ug/ml 30ug/ml
• 200ug/ml 170ug/ml 140ug/ml 110ug/ml
2hr 2hr Nil 2hr Nil

 This type occurs when a drug saturates its elimination

mechanisms (enzyme mediated processes)
Zero Order Kinetics (Cont…)
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❑ t1/2 of a drug following zero order is never constant.

❑ Half-life is proportional to the initial concentration of the drug.
Zero Order Kinetics (Cont…)
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▪ If such a fall in plasma concentration is plotted against time, the

resultant “plasma fall-out curve” is steeply linear, but if logarithm of
plasma concentration are plotted against time , then the curve
becomes curvilinear.
Drugs Showing Zero Order Kinetics
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ZERO Zero order kinetics shown by

W Warfarin
A Alcohol & Aspirin
T Theophylline
T Tolbutamide
POWER Phenytoin

Zero WATT Power

 Maximum velocity (vmax): is the rate at which an
enzyme catalyzes a reaction when it is saturated
with substrate

Km is the substrate concentration at which half

20 of the maximum velocity is achieved (1/2 vmax)
 Zero-order First-order
The half-life is …….. At two places on the curve
Not equal equal
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Constant ……… is lost per unit time
Amount Fraction
The rate of elimination is…….
rate of elimination is independent of rate of elimination is directly
the concentration of drugs in the proportional with concentration of
plasma. The enzyme is saturated by a high drug in plasma. if the dose is
free drug concentration, and the rate of increased, the excretion rate is
elimination remains constant, even if the increased, (that is, with each half-life, the
dosage is increased, this may increase concentration decreases constantly by 50%)
toxicity of drugs.
Kinetics
Nonlinear Linear

Drugs
E.g. Ethanol(alcohol), phenytoin, aspirin E.g. penicillin, aminoglycoside , quinolones
*Most of drugs (95%)
 First Order kinetics Zero Order kinetics
(Linear kinetics) (Non linear kinetics)
1. Constant fraction of drug is eliminated per 1. Constant amount of the drug is
unit time. eliminated per unit time.

2. Rate of elimination is proportional to 2. Rate of elimination is independant of

plasma concentration. plasma concentration.

3. Clearance remains constant. 3. Clearance is more at low

concentrations and less at high conc.
4. Half life remain constant.
4. Half life is less at low conc. and more
5. Most of the drugs follow first order at high conc.
kinetics.
5. Very few drugs follow pure zero order
kinetics e.g. alcohol.

6. Any drug at high conc. (when metabolic

or elimination pathway is saturated)
May show zero order kinetics.
 First and Zero Order Kinetics

𝐶𝑝2−𝐶𝑃1 𝑙𝑜𝑔𝐶𝑝2−𝑙𝑜𝑔𝐶𝑃1
Slope= Slope=
𝑇2−𝑇1 𝑇2−𝑇1

CP

N.Emam
First and Zero Order Elimination

Zero Order First Order

Elimination Rate (E) Constant (Rate= -K) proportional to the concentration remaining on
(fixed amount per time) the body (fixed % per time) (Rate= -K . Cp
remaining)
Equation Cp= Cpₒ − 𝑘t logCp= logCpₒ −
𝑘t
Or Cp= Cpₒ e −kt
2.303

Slope -𝑘 −𝑘/2.303
Unit of 𝐤 Conc/time (µg/mL.hr) Time-1 (hr-1)
t½ Cpₒ /2𝑘 0.693/𝑘 (Constant)
Y-intercept Cpₒ Log Cpₒ (on semi-Log paper)
Graph Shape (cartesian
paper) Linear Curve

Graph Shape (Semi-Log

paper) Curve Linear
Elimination t1/2 = ln = 0.693
k k

Ln2 = natural logarithm of 1/2= (0.693)

k = Elimination rate constant

k = CL
Vd
CL = (fraction of total amount of drug which is removed unit time)
So t1/2 = 0.693 x Vd
CL
T½ is a useful parameter can be obtained for Vd and CL
 Steady state Plasma Concentration
(Cpss)
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❑ If the fixed dose of the drug :administered at

every half-lives, 5 t1/2 : 97% achievement of its
steady state level in the body.
First Order Kinetics
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During drug treatment

steady state plasma conc.: maintained within a

known effective therapeutic range

lower level than this: drug would be ineffective

high level it would lead to overdosage toxicity.

 The Platue Principle
Repeated dosing:

• When constant dose of a drug is

repeated before the expiry of 4 half-life –
peak concentration is achieved after
certain interval

• Balances between dose administered

and dose interval

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 Target Level Strategy
 Low safety margin drugs (anticonvulsants, antidepressants, Lithium,
Theophylline – maintained at certain concentration within therapeutic
range
 Drugs with short half-life (2-3 Hrs) (wide safety margin)–administered
at conventional intervals (6-12 Hrs) – fluctuations are therapeutically
acceptable.
 Long acting drugs:
 Loading dose: Single dose or repeated dose in quick succession – to attain
target conc. Quickly
Loading dose = (target Cp X Vd)/F

 Maintenance dose: dose to be repeated at specific intervals

Maintenance dose = (CPss X Clearance)/F
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• For one compartment distribution, drugs having
1st order elimination and given I.V……
• Two slopes
• Alpha- initial rapidly declining due to
distribution Beta- later less declined due to
elimination

• Half-lives calculated from the terminal

slopesare (beta slope): called the half-time of
thedrug
 Clinical Importance:
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❑ Drugs having very short half-life are given by constant i.v.

infusion to maintain steady state concentration.

❑ Drugs having t1/2 = 30 mins to 2 hrs , it becomes inconvenient to

administer it every half life. In such cases, provides the drug is
having high safety margin and obeying 1st order kinetics , dose
can be so increased that the drug can be administered every 6-8
hours.

❑ The drugs having t1/2 = 4-12 hours, administered at every half32life

interval.
 Clinical Importance (Cont…)
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❑ The drugs having medium half life usually given at 12 hours

interval.

❑ Drugs having 24 hours t1/2, half of the therapeutic dose is given

at every half of t1/2 (half of therapeutic dose / 12 hours).

❑ For drugs having longer t½, with high Vd & slow rate of
clearance also are cumulative in nature. To reach steady state →
Loading dose given → Maintenance dose.
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❑ Loading dose= Desired plasma conc. (mg/L) * aVd (L/kg).
 Criteria for selecting Dosing interval
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❑ Half-life

❑ Safety Margin

❑ Duration of Action

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 Loading dose Maintenance doses
Is the large initial dose that is given Are the doses required to
till the required therapeutic plasma maintain the steady state level
level is rapidly reached. and therapeutic level of the
drug.
After administration of drug the
These doses balance the amount
plasma concentration decreases due to
of drug lost during metabolism
distribution of drugs to other tissues.
and clearance

Initial loading doses are drugs are The patient needs to take regular
given in order to achieve rapid doses of a drug such as
therapeutic level. These doses amoxycillin F500 mg) 8 hourly to
balances the drug distribution. maintain the therapuatic level.

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