In vitro studies have shown that the activities of
cytochrome P450 (
P450) enzymes may be altered after hepatic
ischemia-reperfusion (IR) injury. Here, we investigated the effects of 1 h of partial
ischemia, followed by 3 (IR3) or 24 (IR24) h of in vivo reperfusion, on the in vivo, isolated perfused rat liver (IPRL), and microsomal disposition of
chlorzoxazone (CZX) and its
cytochrome P450 2E1 (CYP2E1)-mediated metabolite,
6-hydroxychlorzoxazone (HCZX), in rats. Although IR3 caused a 30% reduction in the in vivo clearance of CZX, the area under the plasma concentration-time curve of HCZX was not affected. IPRL experiments showed that IR3, in addition to a 30% reduction in the clearance of CZX, causes a 70% decrease in the biliary clearance of HCZX. Microsomal data revealed a 50% decline in the intrinsic clearance of HCZX formation due to an IR3-induced significant decline in maximum velocity. Although IR3 did not affect the microsomal
CYP2E1 protein, it caused approximately 30% reduction in the
cytochrome P450 reductase activity. IR24 did not have any effect on the disposition of CZX or HCZX. In conclusion, metabolism of
xenobiotics and endogenous compounds that are substrates for
CYP2E1, and possibly other P450
isoenzymes, may be reduced shortly after
surgical procedures that require transient interruption of the hepatic blood flow.