Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans

OBJECTIVE: Previous in vitro studies have demonstrated that hepatic P4502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measurement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could serve as a marker of hepatic P4502E1 content. METHODS: Three subject groups were included: recently drinking alcoholics (N = 6), abstinent alcoholics (N = 5), and nonalcoholic subjects with liver disease (N = 5) undergoing liver biopsy. Excess tissue was procured for immunochemical determination of hepatic P4502E1 content. Within an hour of the biopsy, 750 mg CZX was administered orally and serial plasma samples were collected for 6 h. RESULTS: Recently drinking alcoholic subjects had a higher area under the curve for plasma 6-OH-CZX (1.354 +/- 0.258 microg x min x ml(-1)) then abstinent alcoholic subjects (0.296 +/- 0.080 microg x min x ml(-1), p < 0.005) and subjects with nonalcoholic liver disease (0.428 +/- 0.061 microg x min x ml(-1), p < 0.005). The use of the plasma 6-OH-CZX/CZX ratio at 90, 120, and 180 min discriminated between recently drinking alcoholic and nondrinking subjects. Hepatic P4502E1 content significantly correlated with the maximal 6-OH-CZX concentration (r = 0.76, p = 0.001) and other pharmacokinetic parameters. In the recently drinking group, the area under the curve for plasma 6-OH-CZX significantly decreased after 8 days of abstinence. CONCLUSIONS: Measurement of plasma 6-OH-CZX after administration of a CZX challenge can serve as a marker of hepatic P4502E1 activity and thus help avoid adverse drug reactions secondary to P4502E1 induction, particularly in heavy drinkers.