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Chlorzoxazone: a probe drug the metabolism of which can be used to monitor one-point blood sampling in the carbon tetrachloride intoxicated rat

Institute of Community Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki-ken 305-8575, Japan

In this study, we have carried out an investigation to determine if chlorzoxazone (CZX) is a suitable probe drug for predicting hepatic injury in carbon tetrachloride (CCl₄)-intoxicated rats. The animals received oral doses of CCl₄ (0.25, 0.5 and 1 ml/kg) 24 h prior to intraperitoneal administration of CZX. The total CYP and CYP2E1 content, as well as the aniline and CZX hydroxylase activity (V max and CL_int), was reduced depending on the dose of CCl₄ administered. At the highest concentration (128 mM) of diethyldithiocarba mate, a specific inhibitor of CYP2E1, the production of 6-hydroxychlorzoxazone (HCZX) in microsomes from CCl₄ treated rats was reduced by about 85%. The IC₅₀value in microsomes from CCl₄ treated rats was between 3 and 5 M. The production of HCZX and the activity of aniline hydroxylase in CCl₄ treated rats correlated with the amount of rat CYP2E1 protein (r =0.881, P <0.001 and r =0.822, P <0.001, respectively). The elimination of CZX by CCl₄ treated rats was reduced and the HCXZ production in the CCl₄ treated group was less than that in the olive oil-treated control group. The correlations between the intrinsic clearance (CL_int:V max /Km) in vitro and the total body clearance (CL_tot) of CZX hydroxylation and the elimination half-life (t_1/2) of CZX in vivo in CCl₄ treated rats were high (r =0.839, P <0.001 and r = 0.828, P <0.001, respectively). In addition, the metabolic plasma HCZX/CZX ratio did not require multiple blood sampling and, 2 h after CZX administration in vivo, there was also a high correlation with the CL_int (V max / K m) in vitro (r = 0.909, P<0.01). In conclusion, these results from this study demonstrate that CZX is a good probe for monitoring the inhibition of metabolism in rats due to CCl₄ treatment.

Key Words: rat • carbon tetrachloride • CYP2E1 • hepatic enzyme activity • liver disease • chlorzoxazone

Human & Experimental Toxicology, Vol. 20, No. 8, 381-385 (2001)
DOI: 10.1191/096032701682692937


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