Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans

• Published in: The American journal of gastroenterology Vol. 93; no. 11; pp. 2154 - 2161
• Main Authors: MISHIN, V. M, ROSMAN, A. S, BASU, P, KESSOVA, I, ONETA, C. M, LIEBER, C. S
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing 01.11.1998
• Subjects: Alcoholism - enzymology; Biological and medical sciences; Biomarkers - analysis; Chlorzoxazone - pharmacokinetics; Cytochrome P-450 Enzyme System - metabolism; Digestive system; Enzyme Induction; Humans; Investigative techniques, diagnostic techniques (general aspects); Liver Diseases - enzymology; Liver Diseases, Alcoholic - enzymology; Medical sciences; Middle Aged; Muscle Relaxants, Central - pharmacokinetics; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Performance evaluation; Human; Measurement; Concentration factor; Disease; Digestive system; Cytochrome P450; Liver; Cell biology; Biological effect; Metabolism; Chlorzoxazone
• ISSN: 0002-9270; 1572-0241
• DOI: 10.1111/j.1572-0241.1998.00612.x

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. 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. 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. 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.