Order of Kinetics, ADME

SaedGF, BPharm - GSU

Kinetics of Absorption
First-order absorption
First First-order absorption means the absorption rate is
proportional to the amount of drug at the absorption site.

Typically this means that the absorption rate is higher immediately

after the dose is given and the rate then decreases as drug is absorbed.

The fractional rate of decline is constant for a first-order

process.

The oral absorption of drugs often approximates first order

kinetics, especially when given in solution
solution..
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SaedGF, BPharm - GSU

Zero-order absorption process

Sometimes, a drug is absorbed at essentially a constant

rate.

In zero-order absorption process, the fractional rate

increases with time, because the rate is constant but
the amount remaining decreases.

This can be achieved by a constant rate intravenous infusion. It can also be approximated by some
kinds of oral dosing.
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SaedGF, BPharm - GSU

Kinetics of metabolism
First-order kinetics:

The rate of drug metabolism is directly

proportional to the concentration of free drug.

This means that a constant fraction of drug is

metabolized per unit of time.

Zero-order kinetics:
As the amount of drug rises in the plasma,
certain processes that have limited capacity
become saturated (limited amount of enzymes
even if dose increases).

Example: Aspirin, Ethanol

Ethanol, and Phenytoin
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Kinetics of elimination
First Order Elimination

For most drugs, the rate of elimination from the body is

proportional to the amount of drug present in the body (AB).

This type of elimination kinetics is called first-order elimination or

kinetics

The elimination rate constant (kel) is used to denote how quickly

drug serum concentrations decline in a patient.

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First--order elimination
First

The rate of elimination of the drug that follows first order

elimination can be described as:

Elimination rate = dA/dt = - k A , where k is the first-order rate constant.

With first order elimination,

Elimination rate is dependent on the concentration of A present in

the body.
Constant fraction of drug will be removed (e.g. 10% per hour)

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if 1000 mg of a drug is administered and the drug follows firstfirst-order elimination

Time after drug

Amount of drug in

Amount of drug

Fraction of drug

administration (hrs)

body (mg)

eliminated over

eliminated over

preceding hour (mg)

preceding hour

1000

850

150

0.15

723

127

0.15

614

109

0.15

522

92

0.15

444

78

0.15

377

67

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Zero--order elimination
Zero

If large amount of drug is administered, then order of

elimination process of the drugs will change from a first-order
process to a zero-order process. Example: phenytoin

With zero order elimination

The amount of drug eliminated does not change with AB
The fraction removed varies

The rate of elimination of the drug that follows zero order elimination
can be described as:

elimination rate = dA/dt = - k*, where k* is the zero-order rate

constant
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If 1000 mg of a drug is administered and the drug follows zero

zero--order
elimination
Time after drug

Amount of drug in

Amount of drug

Fraction of drug

administration

body (mg)

eliminated over

eliminated over preceding

preceding hour (mg)

hour

(hrs)

1000

850

150

0.15

700

150

0.18

550

150

0.21

400

150

0.27

250

150

0.38

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CLICAL PHARMACOKINETICS Solomon A., 11/8/2015

lecturer CHS MU

Plots of zero and first order elimination

Zero-order kinetics (linear y-axis)

First-order kinetics (log y-axis)

Zero Order
Order

First-order kinetics (linear y-axis)

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1st

Half-Life

Half-life is the time taken for the drug concentration to

fall to one half of its original value
Plasma half life generally, it is measured by

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The time .
To decline the plasma concentration of a drug to. 50% from
the peak plasma concentration (PPC / Tmax)
Time to decline conc. from 100 to 50 = 2 hr
So, t1/2 of this drug is 2 hr

SaedGF, BPharm - GSU

Generally, a drug will be completely eliminated after 6 half

lives

After 1 half-life the conc. will be 50%

After 2 half-lives it will be 25%
After 3 half-lives 12.5% and
After 4 half-lives 6.25%
After 5 half-lives 3.125%
After 6 half-lives 1.56%

Generally, a decline to 6.25% will usually be far below the

therapeutic threshold

For this reason it is usually said that drugs no longer have a

pharmacological effect 4 half-lives after the last dose
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SaedGF, BPharm - GSU

Clearance (CL)
(CL)

The clearance (CL) of a drug is the theoretical volume of

plasma from which drug is completely removed in unit
time.
time

Mathematically, clearance is the division of the rate of

elimination and plasma concentration (Cp).Thus

Rate of eliminatio n ( mg )
h
CL
C p ( mg )
L

Rate of elimin k el . AB

A
CL k el .
k el Vd
Cp
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Clearance
Clearance

Drugs can be cleared from the body by many different

mechanisms, pathways, or organs, including hepatic
biotransformation and renal and biliary excretion.
Renal clearance

rate of elimination by kidney

C
Hepatic clearance = rate of elimination by liver
C
Other organ clearance = rate of elimination by organ
C

CL total = CL renal + CL hepatic + CL pulmonary +CL others

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Clearance

For an agent removed primarily by the kidneys, renal clearance

(Clr) makes up most of the total body clearance.

For a drug primarily metabolized by the liver, hepatic clearance

(Clm) is most important.

Lets consider a single organ, kidneys and Q (mL/minute) which is

blood flow through the organ, Cin , the drug Conc. in the blood
entering the organ and Cout , the drug Conc. in the exiting blood

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Clearance
Clearance

Hence an organ's ability to remove a drug (extraction ratio, E) can

be measured by relating Cin and Cout.

in

C
C in

out

If Cout = 0, the drug will be totally removed and the E will be 1.

If Cout = Cin, there is no drug removal and the E will be 0.
E generally lies somewhere b/n 0 and 1
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Clearance
Clearance

Therefore , The drug clearance of any organ is determined by

blood flow and the extraction ratio:
Organ clearance = blood flow x extraction ratio = Q E

In general, Organ clearance is high when the blood flow

and the extraction ratio are high.

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Reading Assignment

Design and Optimization of Dosage Regimen

Variable Dose
Fixed Dose
Optimization of Dosage Regimen

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Loading Dose
Maintenance Dose

Steady State Concentration

SaedGF, BPharm - GSU