NONLINEAR

PHARMACOKINETICS
Nonlinear Pharmacokinetics

The term 'linear pharmacokinetics' indicates that for a given drug and
individual all concentrationtime profiles that are normalised for time and
size of dose should be superimposible.
Therefore, the term 'nonlinear pharmacokinetics' implies that such profiles
are not superimposible, due to one or more time- or dose-related
dependences .
The sources of nonlinear pharmacokinetic behaviour can be categorised
according to which kinetic processes (absorption, distribution or elimination)
are involved.
(Ludden, 1991)
1. Nonlinear Absorption or
Bioavailability
Nonlinearities in systemic drug input may arise from
saturation of a carrier system,
poor solubility in luminal fluid,
saturation of portal plasma protein binding,
saturation of metabolic processes responsible for presystemic
metabolism
doses or time-related changes in gastric emptying or gastrointestinal
blood flow or mobility.
The first 3 mechanisms can lead to a less than proportional increase
in the amount of drug reaching the systemic circulation as dose is
increased, the fourth yields a greater than proportional increase
and the last mechanism may result in either increased or decreased
absorption, depending on other characteristics of the drug and
dosage form.
(Ludden, 1991)
1.1 Poor Aqueous Solubility or Slow
Release
Drugs that are poorly soluble or dosage forms that release too
slowly can exhibit nonlinear absorption due to movement past the
upper gastrointestinal tract, the usual site for optimal absorption,
before absorption is complete.
In addition, if a dosage form releases in such a manner that a
saturated solution of drug in the gastrointestinal tract is maintained
and absorption is via passive diffusion, then the systemic
appearance of drug may be approximately zero-order.
In either case, increases in dose would not necessarily result in a
proportional increase in the amount absorbed.
Again, dividing the dose may improve the extent of absorption by
spreading the dose over a larger portion of the gastrointestinal
tract.
(Ludden, 1991)
1.2 Saturation of Portal Plasma
From a theoretical view it is possible that concentration-dependent plasma protein
binding in portal blood could alter the first-pass extraction of a drug in a dose-
dependent manner.
If the resulting systemic concentrations were well below the equilibrium dissociation
constant (kd) due to a relatively large volume of distribution (Vd), the range of
unbound fraction values (fu) operative in portal blood during rapid absorption
would be much higher than during the postabsorption elimination phase. This could
give rise to increased presystemic extraction as the dose increased, and lead to a
reduction in relative bioavailability.
Systemic clearance would be essentially unaltered for the major portion of the time
that drug was present in the body unless the drug had a relatively short halflife
(t1/2). This mechanism could be important for drugs that are rapidly absorbed and
highly bound, and have intermediate extraction ratios.
(Ludden, 1991)
 The clinical significance of this interaction would
be similar to that for the previous 2 mechanisms.
The relative steady-state area under the
concentration-time curve (AUe) for both total and
free drug would decline as oral dose was
increased.
Again, dividing the dose or, in this case,
decreasing the rate of absorption, could minimise
or eliminate the nonlinearity.
(Ludden, 1991)
1.3 Saturation of Presystemic
Metabolism
Many drugs undergo significant presystemic metabolism or
degradation in the gut lumen, the gut mucosa or the liver
If 1 or more of these processes is at least partially saturable with
the concentrations achieved at these sites, nonlinear bioavailability
may result.
Free and total drug concentrations may rise rapidly as the dose or
rate of absorption is increased.
As noted above in regard to saturable portal plasma protein
binding, concentration at the absorption site or in the liver may be
much higher during the absorption phase than during the subsequent
elimination of drug from the systemic circulation.
(Ludden, 1991)

1.4 Dose-Related Changes in Gastric Emptying,

Gastrointestinal Motility or Blood Flow

Dose-related changes in blood flow, gastric

empyting and intestinal transit time can give rise to
dose-dependent changes in peak concentrations
(Cmax) and times to peak concentrations (tmax)
which are particularly sensitive to the rate of
absorption.
(Ludden, 1991)
2. Nonlinear Distribution
2.1 Saturable Blood Cell Binding
Saturation of blood cell binding can cause the blood-to-
plasma concentration ratio for a drug to be concentration
dependent. This can give rise to complex, nonlinear kinetics
of drug elimination relative to free drug concentration if the
elimination is nonrestrictive.
However, if elimination is a function of free drug in plasma
water, the kinetics of elimination will be linear relative to
free and total plasma concentrations but nonlinear relative
to whole blood concentrations.

(Ludden, 1991)
2.3 Saturable Tissue Binding
Saturation of tissue uptake or binding sites would
be evidenced by a decrease in volume of
distribution at steady-state (Vss) as dose (and
concentration) increases.
In the case of constant clearance, this results in an
increase in t1/2 as concentration decreases, giving
rise to concave concentration-time-elimination
profiles that in many respects mimic those seen due
to pharmacokinetic heterogenecity, i.e.
multicompartment characteristics
(Ludden, 1991)
3. Nonlinear Elimination
3.1 Saturable Elimination
Saturation or partial saturation of 1 or more pathway for the systemic
elimination of drug is one of the major causes of nonlinear elimination.
The Michaelis-Menten equation for rate of drug elimination (dAe/dt) is:

dAe/dt = VmaxC/(Km + C)

where C is the measured drug concentration,

V max is the maximum rate of elimination in units of amount/time
Km is the concentration at which the rate of elimination is half maximal
(Ludden, 1991)
 if a 1-compartment system with Michaelis-Menten elimination is
applied, and daily dose can be represented as a constant rate of
drug input (Ro), then the following rate expression results:

dA/dt = Ro - V maxC/(Km + C)

where dA/dt is the rate of change of drug amount in the body.

Obviously, a drug eliminated by only saturable pathways can
accumulate indefinitely if dosed at a daily rate that exceeds the
maximal rate of elimination.
(Ludden, 1991)
 However, virtually all drugs are likely to have at least a
small parallel first-order pathway, so a more
appropriate expression for the rate of elimination
would be:

dAe/dt = V maxC/(Km + C) + CL C

where CL is the clearance for the linear pathway(s).

(Ludden, 1991)
 At low concentrations relative to Km the elimination
of drug is pseudo-first-order with constant
clearance, i.e:

dAe/dt = [(Vmax/Km) + CL]C

or
(dAe/dt)/C Vmax/Km + CL

(Ludden, 1991)
 Nonlinear pharmacokinetic behaviour will be most
evident when concentrations are close to or above
the Km value. At high concentrations relative to Km,
the rate of elimination approaches:

dAe/dt V max + CL C

(Ludden, 1991)
 At very high concentrations, the rate of elimination
may again be first order when the rate of
elimination via the linear pathway greatly exceeds
the V max value for the saturable pathway.

dAe/dt CL C
(Ludden, 1991)
3.2 Cofactor Depletion
If cofactor availability is decreased, the rate may slow substantially.
The serious hepatotoxicity induced by paracetamol (acetaminophen)
is a result of cofactor depletion.
A small fraction of paracetamol is metabolised by cytochrome
P450-dependent mixed function oxidase to a reactive metabolite
believed to be N-acetyl-benzoquinoneimine.
This metabolite is normally inactivated by rapid conjugation with
reduced glutathine.
Hepatic glutathione is depleted by high doses of paracetamol and
the excess metabolite has an increased probability of binding
covalently to hepatic proteins and enzymes.

(Ludden, 1991)
3.3 Product Inhibition
Metabolites of a drug may cause inhibition of parent drug metabolism.
If the inhibition is competitive in nature then dAe/dt will be a function of the
metabolite concentration (Cm) and the equilibrium dissociation constant for the
enzymemetabolite complex (kp), as shown in the following expression

dAe/dt = V maxC/[Km( I + Cm/kp) + C

If parent drug concentrations are well below the Km value and the metabolite has a
long t1/2 the parent drug may exhibit apparent first-order pharmacokinetics after a
given dose but larger doses may yield longer t1/2 values.
In general, product inhibition can give rise to both concentration- and time-
dependent pharmacokinetic behaviour, depending on the mechanism of inhibition,
the Km and kp values and the dose of the parent drug.

(Ludden, 1991)
References
Ludden, T. M. (1991). Clinical Pharmacokinetics.
USA: Adis International Limited.