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A nonlinear physiologic pharmacokinetic model: I. Steady-state.

J G Wagner, G J Szpunar, J J Ferry

Journal of Pharmacokinetics and Biopharmaceutics

|February 1, 1985

Summary

This study extends a pharmacokinetic model using Michaelis-Menten elimination kinetics. The new model explains drug concentration changes, particularly for first-pass drugs, offering better physiologic interpretation.

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Area of Science:

Pharmacokinetics
Pharmacodynamics
Drug Metabolism

Background:

The standard two-compartment model often assumes first-order elimination kinetics.
Real-world drug metabolism can exhibit nonlinear behavior, especially at higher concentrations.

Purpose of the Study:

To extend the two-compartment model by incorporating Michaelis-Menten elimination kinetics.
To derive and report equations for steady-state concentrations and clearances under zero-order input.
To provide a physiologically interpretable model for both linear and nonlinear pharmacokinetic data.

Main Methods:

Mathematical derivation of steady-state equations for intravenous and oral administration.
Integration of Michaelis-Menten kinetics into a two-compartment model.
Analysis of the influence of Vm, Km, and liver blood flow (Q) on drug concentrations.

Main Results:

Steady-state concentration in compartment #1 is a nonlinear function of Vm, Km, and Q for IV administration.
For oral administration, steady-state concentration depends only on Vm and Km, independent of Q.
Oral bioavailability is shown to be a function of Vm, Km, and Q.

Conclusions:

The extended model provides a more realistic physiologic pharmacokinetic interpretation of drug behavior.
This model can explain complex pharmacokinetic data, especially for drugs undergoing significant first-pass metabolism.
The framework is adaptable for future analyses of single doses, literature data, toxicology, and clinical applications.

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