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

The two-compartment model of Rowland et al., (2) has been extended by replacing first order elimination with Michaelis-Menten elimination kinetics. All of the equations for steady-state concentrations and clearances for zero order (constant rate) input orally (into compartment #2) and intravenously (into compartment #1) are derived and reported. The steady-state concentration in compartment #1, following intravenous administration, is shown to be a nonlinear function of maximal velocity of metabolism, Vm, the Michaelis constant, Km, and liver blood flow, Q; and, following oral administration is dependent only upon Vm and Km and is independent of Q. However, oral bioavailability is a function of Vm, Km, and Q. The model allows physiologic pharmacokinetic interpretation of both linear and nonlinear data; and, together with simple modification of the model, can explain much observed pharmacokinetic data to date particularly for first-pass drugs. Future articles in the series will be concerned with single doses, evaluation of literature data in terms of the model, application of the theory in toxicology and in clinical pharmacokinetics and therapeutics.