PHARMACOKINETICS AND METABOLISM OF VINYL FLUORIDE IN-VIVO AND IN-VITRO

Vinyl fluoride (VF) is an inhalation carcinogen at concentrations of 2 5 ppm or greater in rats and mice. The main neoplastic lesion induced in rodents was hepatic hemangiosarcomas, and mice were more sensitive than rats. In a first set of experiments, groups of three rats or five mice were exposed to VF in a closed-chamber gas uptake system at star ting concentrations ranging from 50 to 250 ppm. Chamber concentrations of VF were measured every 10-12 min by gas chromatography. Partition coefficients were determined by the vial equilibration technique and u sed as parameters for a physiologically based pharmacokinetic (PBPK) m odel. Mice showed a higher whole-body metabolic capacity compared to r ats (V-maxc=0.3 vs 0.1 mg/hr-kg). Both species had an estimated K-m of less than or equal to 0.02 mg/liter. The specificity for the oxidatio n of VF in vivo was determined by selective inhibition or induction of CYP 2E1. Inhibition with 4-methylpyrazole completely impaired VF upta ke in rats and mice, whereas induction with ethanol (rats only) increa sed the metabolic capacity by two- to threefold. The pharmacokinetics of VF were also investigated in vitro. Microsomes from rat and mouse l iver were incubated in a sealed vial with VF and an NADPH- regeneratin g system. Headspace concentrations (10-300 ppm) were monitored over ti me by gas chromatography. Consistent with the in vivo data, VF was met abolized faster by mouse microsomes than by rat microsomes (V-max=3.5 and 1.1 nmol/hr-mg protein, respectively). The rates of metabolism by human liver microsomes were generally in the same range as those found with rat liver microsomes (V-max=0.5-1.3 nmol/hr-mg protein), but one sample was similar to mice (V-max=3.3 nmol/hr-mg protein). Metabolic rates in human microsomes were found to correlate with the amount of C YP 2E1 as determined by Western blotting and by chlorzoxazone 6-hydrox ylation. It is concluded that the greater metabolic capacity of mice f or VF both in vivo and in vitro may contribute to their greater suscep tibility to tumor formation. CYP 2E1 is clearly the main isozyme invol ved in the oxidation of VF in all species tested. VF pharmacokinetics and metabolism in humans may depend upon the interindividual variabili ty in the expression level of CYP 2E1. The excellent correspondence be tween in vivo and in vitro kinetics in rodents improves substantially the degree of confidence for human in vivo predictions from in vitro d ata. (C) 1997 Academic Press.