Vm. Mishin et al., CHLORZOXAZONE PHARMACOKINETICS AS A MARKER OF HEPATIC CYTOCHROME P4502E1 IN HUMANS, The American journal of gastroenterology, 93(11), 1998, pp. 2154-2161
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.