Distribution pharmacokinetics of warfarin in the rat, a non-linear multicompartment model

Preliminary analysis and linear two-compartment solutions of warfarin plasma concentrations recorded in the rat after intravenous bolus injections of 1, 2, 8 and 40 mg/kg of sodium warfarin revealed marked non-linearities. The half-life of total warfarin concentration in the plasma from 1-12h remained unchanged with all the doses used, but that of free warfarin was shorter with 40 mg/kg, possibly as the result of an increase in the binding of the drug to plasma proteins as the high total warfarin concentration decreased. The apparent volume of distribution generally increased with increasing dose, and differed according to the method used for its calculation. Liver warfarin data could be solved with Langmuir type saturation kinetics, but the saturation phenomena were slight in the concentration range studied. A non-linear multicompartment model was constructed, the physiological spaces of which were plasma, interstitial fluid and tissue. The binding of free warfarin to plasma proteins, interstitial fluid proteins and tissue structures was assumed to occur instantaneously, with saturable binding to plasma and interstitial fluid proteins, and a constant binding to tissues. The fluxes between the free warfarin pools of plasma and interstitial fluid as well as elimination were assumed to be linear. Following parameters were simulated simultaneously, using an analog hybrid computer: two for the above-mentioned fluxes, four for zero time drug mass distribution between plasma and interstitial fluid, and one for tissue binding. According to the best fits, warfarin is preferentially distributed into plasma, interstitial fluid and highly perfused tissues. The solution suggests that non-linearities in the pharmacokinetics of warfarin, a highly plasma protein-bound drug, first occur in plasma and interstitial fluid. Therefore, it is believed that the quantitative non-linear multicompartment approach presented in this paper might be useful in studying the kinetic behaviour of other highly plasma protein-bound drugs, too.