Nonlinear pharmacokinetics

By Ms. Eesha Tariq Bhatty

Mphil, Pharm D. R.Ph.

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 Introduction: Linear
• Pharmacokinetic parameters, such as elimination half life
(t1/2), the elimination rate constant (K), the apparent
volume of distribution (V), and the systemic clearance
(Cl) of most drugs are not expected to change when
different doses are administered and/or when the drug is
administered via different routes as a single dose or
multiple doses
• The kinetics of these drugs is described as linear, or
dose-independent, pharmacokinetics and is
characterized by the first-order process
• The term linear simply means that plasma concentration
at a given time at steady state and the area under the
plasma concentration versus time curve (AUC) will both
be directly proportional to the dose administered

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Introduction: Linear

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 Introduction: Nonlinear
• For some drugs, however, the above
situation may not apply
• For example, when the daily dose of
phenytoin is increased by 50% in a patient
from 300 mg to 450 mg, the average
steady-state plasma concentration, (Cp)ss,
may increase by as much as 10-fold
• This dramatic increase in the concentration
(greater than directly proportional) is
attributed to the nonlinear kinetics of
phenytoin
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 Introduction: Nonlinear
• For drugs that exhibit non-linear or dose dependent
kinetics, the fundamental pharmacokinetic
parameters such as clearance, the apparent
volume of distribution, and the elimination half life
may vary depending on the administered dose
• This is because one or more of the kinetic
processes (absorption, distribution and/or
elimination) of the drug may be occurring via a
mechanism other than simple first-order kinetics
• For these drugs, therefore, the relationship
between the AUC or the plasma concentration at a
given time at steady state and the administered
dose is not linear
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Introduction: Nonlinear

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Introduction: Nonlinear
Administration of different
doses of drugs with nonlinear
kinetics may not result in
parallel plasma concentration
versus time profiles expected
for drugs with linear
pharmacokinetics

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 Introduction: Nonlinear
• Nonlinearity may arise at any one of the pharmacokinetic steps,
such as absorption, distribution and/or elimination
• For example, the extent of absorption of amoxicillin decreases
with an increase in dose
• For distribution, plasma protein binding of disopyramide is
saturable at the therapeutic concentration, resulting in an
increase in the volume of distribution with an increase in dose
of the drug
• As for nonlinearity in renal excretion, it has been shown that the
antibacterial agent dicloxacillin has saturable active secretion in
the kidneys, resulting in a decrease in renal clearance as dose
is increased
• Both phenytoin and ethanol have saturable metabolism, which
means that an increase in dose results in a decrease in hepatic
clearance and a more than proportional increase in AUC

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 Nonlinearity in metabolism
Capacity-limited metabolism
• Capacity-limited metabolism is also called
saturable metabolism, Michaelis–Menten
kinetics
• Nonlinearity in metabolism, is one of the
most common sources of nonlinearity

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 Nonlinearity in metabolism
Capacity-limited metabolism
• The rate of metabolism, or the rate of elimination
if metabolism is the only pathway of elimination,
is defined by the Michaelis–Menten equation:

Vmax C
Metabolism
• where Vmax rate  rate (unit:
is the maximum
m  is
amount/time) of metabolism;KKm C the
Michaelis–Menten constant (unit: same as the
concentration [amount/volume]), and C is the
drug concentration

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 Nonlinearity in metabolism
Capacity-limited metabolism
• Two cases:
– Km>>C
– Km<<C

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Nonlinearity in metabolism
Capacity-limited metabolism

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 Significance of Various Parameters in Michaelis-
Menten Equation
1. Significance of Km- Measure of Substrate affinity:
•From Michaelis-Menten equation: If v0 is set equal to ½ Vmax, then the relation
Vmax /2 = Vmax [S]/ Km + [S] can be simplified to
Km + [S] = 2[S], or Km = [S]
•This means that at one half of the maximal velocity, the substrate concentration
at this velocity will be equal to the Km.
•Km represents the substrate concentration at which half of the enzyme active
sites are filled with the substrate.
•The significance of Km change depends on the different rate constants and
which step is the slowest rate-limiting step.
•In the simplest assumption, the rate of ES breakdown to product (k2) is the rate-
determining step of the reaction, so
k-1 >> k2 and
Km = k-1/k1.

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• This relation is also called dissociation constant (Kd) for the ES
complex and can be used as a relative measure of the affinity of a
substrate for an enzyme (identical to Kd).
• However if k2 >> k-1 or k2 and k-1 are similar, then Km remains
more complex and cannot be used as a measure of substrate
affinity.
• Km is a dissociation constant, so the smaller the Km the stronger
the interaction between E and S.
• Each enzyme has a characteristic Km for a given substrate that
show how tight the binding of the substrate is to the enzyme.

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Significance of Vmax:
•The maximal rate, Vmax reveals the
turnover No. of an enzyme i.e. the number
of substrate molecules being catalysed per
second.

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Definition and Significance of kcat (Turnover number)
•The constant, kcat (sec-1), is also called the turnover
number because under saturating substrate conditions, it
represents the number of substrate molecules converted to
product in a given unit of time on a single enzyme
molecule.
•In practice, kcat values (not Vmax) are most often used for
comparing the catalytic efficiencies of related enzyme
classes or among different mutant forms of an enzyme.

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kcat/Km (specificity constant)
•used to rank an enzyme according to how good it is
with different substrates or it is a measure of enzyme
efficiency.
•The ratio of kcat/Km is equivalent to the rate constant
for the reaction between the free E and the free S.
•A comparison of kcat/Km for the same enzyme with
different substrates, or for two enymes with their
different substrates , is widely used as a measure of
enzyme catalytic efficiency

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