The privileged access model of 1,3-butadiene disposition

In previous attempts to model disposition of 1,3-butadiene in mice and rats , parameter values for 1,2-epoxybut-3-ene metabolism were optimized to repr oduce elimination of this gas from closed chambers. However, each of these models predicted much higher concentrations of circulating epoxybutene than were subsequently measured in animals exposed to butadiene. To account for this discrepancy, a previous physiologically based pharmacokinetic model o f butadiene disposition was modified to describe a transient complex betwee n cytochrome P450 and epoxide hydrolase on the endoplasmic reticulum:membra ne. In this model the epoxide products are directly transferred from the P4 50 to the epoxide hydrolase in competition with release of products into th e cytosol. The model includes flow-restricted delivery of butadiene and epo xides to gastrointestinal tract, liver, lung, kidney, fat, other rapidly pe rfused tissues, and other slowly perfused tissues. Blood was distributed am ong compartments for arterial, venous, and capillary spaces. Oxidation of b utadiene and epoxybutene and hydrolysis and glutathione conjugation of epox ides were included in liver, lung, and kidney. The model reproduces observe d uptake of butadiene and epoxybutene from closed chambers by mice and rats and steady-state concentrations of butadiene, epoxybutene, and 1,2;3,4-die poxybutane concentrations in blood of mice and rats exposed by nose only. S uccessful replication of these observations indicates that the proposed pri vileged access of epoxides formed in situ to epoxide hydrolase is a plausib le mechanistic representation for the metabolic clearance of epoxide-formin g chemicals.