CHLORZOXAZONE PHARMACOKINETICS AS A MARKER OF HEPATIC CYTOCHROME P4502E1 IN HUMANS

Objective: Previous in vitro studies have demonstrated that hepatic P4 502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measur ement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could ser ve as a marker of hepatic P4502E1 content. Methods: Three subject grou ps were included: recently drinking alcoholics (N = 6), abstinent alco holics (N = 5), and nonalcoholic subjects with liver disease (N = 5) u ndergoing 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 co llected for 6 h. Results: Recently drinking alcoholic subjects had a h igher area under the curve for plasma 6-OH-CZX (1.354 +/- 0.258 mu g . min . ml(-1)) then abstinent alcoholic subjects (0.296 +/- 0.080 mu g . min . ml(-1), p < 0.005) and subjects with nonalcoholic liver disea se (0.428 +/- 0.061 mu g . min . ml(-1), p < 0.005). The use of the pl asma 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 concentrati on (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: Measu rement of plasma 6-OH-CZX after administration of a CZX challenge can serve as a marker of hepatic P4502E1 activity and thus help avoid adve rse drug reactions secondary to P4502E1 induction, particularly in hea vy drinkers. (C) 1998 by Am. Cell. of Gastroenterology.