Nonlinear Pharmacokinetics

NONLINEAR
PHARMACOKINETICS
Group 1
Winny Rhamadani (1511011005)
Agung Tri Sasongko (1511011006)
Nadya Prafita (1511011007)
Hidayatul Fadila (1511011009)
Nurul Atikah (15110110014)
Adeline Rizki Setiani (15110110016)
Introduction
Linear pharmacokinetic models using simple first-
order kinetics were introduced to describe the
course of drug disposition and action.
These linear models assumed that the
pharmacokinetic parameters for a drug would
not change when different doses or multiple
doses of a drug were given.
The nonlinear pharmacokinetic behavior is termed
dose-dependent pharmacokinetics.
(Shargel, 2004)
Causes of Nonlinear Pharmacokinetic
Saturation of plasma protein-binding or

carrier-mediated systems
Pathologic alteration in drug absorption,
distribution, and elimination
(Shargel, 2004)
Characteristic of Drugs that Demonstrate
Saturation Kinetics
1. Elimination of drug does not follow simple first-order kinetics
that is, elimination kinetics are nonlinear.
2. The elimination half-life changes as dose is increased. Usually, the
elimination half-life increases with increased dose due to
saturation of an enzyme system.
3. The area under the curve (AUC) is not proportional to the amount
of bioavailable drug.
4. The saturation of capacity-limited processes may be affected by
other drugs that require the same enzyme or carrier-mediated
system.
5. The composition and/or ratio of the metabolites of a drug may
be affected by a change in the dose.
(Shargel, 2004)
The Large Dose Curve
A curve is obtained with
an initial slow
elimination phase
followed by a much
more rapid
elimination at lower
blood concentrations.
(Shargel, 2004)
The Small Dose Curve
With a small dose of the
drug, apparent first-
order kinetics are
observed, because no
saturation kinetics
occur
(Shargel, 2004)
Saturable Enzymatic Elimination Processes
The elimination of drug by a saturable enzymatic

process is described by MichaelisMenten kinetics.
Explanation:
C p = the concentration of drug
V max = the maximum elimination rate
K M = the Michaelis constant
(Shargel, 2004)
Cont . . . .
Because the ratio of the elimination rate to drug
concentration changes as the drug concentration
changes, the rate of drug elimination also
changes and is not a first-order or linear process.
In contrast, a first-order elimination process would
yield the same elimination rate constant at all
plasma drug concentrations.
(Shargel, 2004)
Cont . . . .
When the drug concentration C p is large in

relation to K M, saturation of the enzymes
occurs and the value for K M is negligible. The
rate of elimination proceeds at a fixed or
constant rate equal to V max
(Shargel, 2004)
Drug Elimination by Capacity-Limited
Pharmacokinetics
If a single IV bolus injection of drug is given at

t=0, the drug concentration (C p) in the plasma
at any time t
(Shargel, 2004)
Cont . . . .
The amount of drug in the body after an IV

bolus injection to simulate the decline of drug
in the body after various size doses are given,
provided the K M and V max of drug are known.
(Shargel,2004)
Cont . . . .
The time for the dose of the drug to decline to a

certain amount of drug in the body, where D 0 is the
amount of drug in the body at t = 0. Thus, there is an
inverse relationship between the time for the dose to
decline to a certain amount of drug in the body and
the Vmax.
(Shargel, 2004)
Curve that Using Vmax
Amount of drug in the
body versus time for a
capacity-limited drug
following an IV dose.
Data generated using
Vmax of 100 (O) and 200
mg/hr. K m is kept
constant.
(Shargel, 2004)
Curve that Using KM
Amount of drug in the
body versus time for a
capacity-limited drug
following an IV dose.
Data generated using KM
of 38 mg/L () and 76
mg/L (O). V max is kept
constant.
(Shargel, 2004)
Cont . . . .
An increase in K M (with no change in V max) will
increase the time for the drug to be
eliminated from the body.
The one-compartment open model with
capacity-limited elimination pharmacokinetics
adequately describes the plasma drug
concentrationtime profiles for some drugs.
(Shargel, 2004)
Determination of K M and V max
Equation elimination rate relates the rate of drug

biotransformation to the concentration of the drug in the
body, the same equation may be applied to determine the
rate of enzymatic reaction of a drug in vitro.
(Shargel, 2004)
Curve about the rate Drug Metabolism
Plot of rate of drug
metabolism at
various drug
concentrations. (K M
= 0.5 mol/mL, V max =
3 mol/mL per
minute.)
(Shargel, 2004)
Curve about 1/v versus 1/C
Plot of 1/v versus 1/C for

determining KM and
Vmax.
(Shargel, 2004)
The Rearranged Equation
This equation is the rearranged from the determination of K M and

Vmax equation. A plot of C/v versus C would yield a straight line
with 1/V max as slope and K M/V max as intercept. A plot of v versus
v/C would yield a slope of K M and an intercept of V max.
(Shargel, 2004)
Cont . . . .
Plot of v versus v/C for
determining KM and
Vmax, with the yield a
slope of K M and an
intercept of V max.
(Shargel, 2004)
Interpretation of K M and V max
An understanding of MichaelisMenten kinetics
provides insight into the nonlinear kinetics and
helps to avoid dosing a drug at a concentration
near enzyme saturation.
A subject with the same V max, but different K M, the
rate of metabolism when Vmax is constant and KM
is changed . The rate of metabolism is faster for
the lower K M, but saturation starts at lower
concentration.
(Shargel, 2004)
Referency
Shargel, Leon, et al. 2004. Applied Biopharmaceutics
and Pharmacokinetics 5th edition. New York:
McGraw-Hill Book Company.

Nonlinear Pharmacokinetics

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Nonlinear Pharmacokinetics

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What are some causes of nonlinear pharmacokinetics?

What are characteristics of drugs that demonstrate saturation kinetics?

NONLINEAR

Saturation of plasma protein-binding or

The elimination of drug by a saturable enzymatic

When the drug concentration C p is large in

If a single IV bolus injection of drug is given at

The amount of drug in the body after an IV

The time for the dose of the drug to decline to a

Equation elimination rate relates the rate of drug

Plot of 1/v versus 1/C for

This equation is the rearranged from the determination of K M and

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