Variability in the disposition of chlorzoxazone

Chlorzoxazone is 6-hydroxylated by cytochrome P450 2E1 (CYP 2E1), which bioactivates many toxic and carcinogenic molecules. Seventeen volunteers of varying age, ethnicity, and gender received a 250 mg tablet of chlorzoxazone and their blood and urine were sampled frequently for 8 h. V/F = 42 ± 21 L and CL/F = 412 ± 120 mL min^?1. Comparison of these values with a study by other investigators using a suspension dosage form suggested that relative F_tablet ± 0.7. The fraction excreted in the urine as 6-hydroxychlorzoxazone (f_2,6-OH) was 0.39 ± 0.20 and that portion of the total CL accounted for by CYP 2E1-mediated metabolism (CL_6-OH) was 163 ± 95 mL min^?1. Thus, while V/F and CL/F varied by factors of less than five, f_e,6-OH varied 16-fold and CL_6-OH varied 28-fold. These results suggested that there was considerable inter-individual variability in the metabolism of chlorzoxazone to 6-hydroxychlorzoxazone. This variability will significantly affect the construction of physiologically based pharmacokinetic models that use the 6-hydroxylation of chlorzoxazone as a marker for an individual's CYP 2E1 phenotype.