Toxicokinetic modeling of dose-dependent formate elimination in rats: in vivo-in vitro correlations using the perfused rat liver.
The dose-dependent elimination of formate was investigated in the rat using both in vitro and in vivo systems. The in situ perfused liver was used to define the kinetics of hepatic metabolism and obtain initial in vitro estimates 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 formate in 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 observed in vivo data was obtained (overall r2 = 0.978). AR dose dependencies of the data could be adequately fitted using a single set of model parameters. Initial estimates of the Michaelis-Menten parameters, Vmax and Km, obtained from the perfused liver system, were within 40% of the final fitted values of these parameters in the in vivo model, indicating the utility of the perfused liver system for performing in vitro-in vivo correlations.
Damian
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Institute of Toxicology and Environmental Health, University of California, Davis 95616, USA.
Raabe
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OG
D000042:Absorption; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005561:Formates / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D005919:Glomerular Filtration Rate / Q000502:physiology; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D051381:Rats
D005561:Formates; C030544:formic acid