Toxicokinetic Modeling of Dose-Dependent Formate Elimination in Rats:In Vivo–in VitroCorrelations Using the Perfused Rat Liver

Abstract

The dose-dependent elimination of formate was investigated in the rat using bothin vitroandin vivosystems. Thein situperfused liver was used to define the kinetics of hepatic metabolism and obtain initialin vitroestimates of the hepatic metabolism kinetic parameters. Formate was eliminated from the perfused rat liver following Michaelis–Menten kinetics. Estimates of the Michaelis–Menten parameters obtained from the perfused liver studies were used in a two-compartment pharmacokinetic model of the dose-dependent elimination of formatein vivo.This model consisted of a central, well-mixed compartment and a urine compartment. Other features of the model included (1) endogenous production of formate, (2) Michaelis–Menten hepatic metabolism of formate, and (3) renal excretion consisting primarily of glomerular filtration and saturable tubular reabsorption. A good fit of the model to the observedin vivodata was obtained (overallr2= 0.978). All dose dependencies of the data could be adequately fitted using a single set of model parameters. Initial estimates of the Michaelis–Menten parameters,VmaxandKm, obtained from the perfused liver system, were within 40% of the final fitted values of these parameters in thein vivomodel, indicating the utility of the perfused liver system for performingin vitro–in vivocorrelations.