Variability in the disposition of chlorzoxazone

✍ Scribed by Jantine D. De Vries; Laurent Salphati; Seichi Horie; Charles E. Becker; Betty-Ann Hoener

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: English
• Weight: 565 KB
• Volume: 15
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510150706

✦ Synopsis

Abstract

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.