BACKGROUND: Chlormethiazole has been shown in in vitro studies, with use of rat and human liver microsomes, to specifically inhibit cytochrome P4502E1 (CYP2E1)-mediated activity by inhibition of the rate of CYP2E1 gene transcription. It is known that CYP2E1 is involved in the activation of many low-molecular-weight toxins and carcinogens and may be involved in the development of alcohol-induced liver disease. METHODS: The pharmacokinetics of a single oral dose of 250 mg chlorzoxazone, a marker of the activity of CYP2E1, were measured in five healthy drug-free volunteers and in 16 patients with alcoholism receiving 1.2 gm or 2.4 gm chlormethiazole per day for 1, 2, or 3 days. The patients were starting an alcohol-withdrawal program and were supposed to have an induced CYP2E1 activity. RESULTS: The results suggest that chlormethiazole strongly decreased chlorzoxazone clearance in the patients with alcoholism compared with clearance in the control subjects (3.98 +/- 1.8 L/hr versus 12.7 +/- 5.6 L/hr; p < 0.005), prolonged the elimination half-life (3.91 +/- 1.23 hours versus 1.12 +/- 0.34 hours; p < 0.001), and caused a threefold increase in the area under the concentration versus time curve of chlorzoxazone (73.0 +/- 35.5 mg.hr/L versus 21.3 +/- 13.7 mg.hr/L; p < 0.005). They also suggest that chlormethiazole significantly decreased the area under the concentration versus time curve of the metabolite 6-hydroxy-chlorzoxazone (4.56 +/- 1.27 mg.hr/L versus 7.1 +/- 1.84 mg.hr/L; p < 0.05). CONCLUSION: Chlormethiazole administration seems to result in a marked reduction of CYP2E1 activity in subjects with high CYP2E1 activity and could at least partially explain the claimed hepatoprotective action of this drug.