Phenytoin causes a rapid increase in 6 beta-hydroxycortisol urinary excretion in humans--a putative measure of CYP3A induction.

This study was conducted in eight healthy volunteers to assess the time course of induction of cytochrome P-450 by phenytoin. subjects received 200 mg of phenytoin every 8 h for 11 doses and 100 mg every 8 h for 8 doses. Trough concentrations of phenytoin in plasma were measured by HPLC. Urine samples were collected between 08:00 and 12:00 on days -1, 1, 2, 3, 4, 5, and 7. Urinary concentrations of 6 beta-hydroxycortisol (6 beta-OHC) and cortisol (C) were determined by HPLC and were reported as a ratio (6 beta-OHC/C); this ratio is a marker for the 3A isozyme family of cytochrome P-450 (CYP3A). Mean plasma phenytoin concentrations on day 7 were 15.4 +/- 7.20 micrograms/mL. Mean 6 beta-OHC/C ratios increased by a factor of 2.37 from baseline during the course of the study. Values for the ratios on days 4, 5, and 7 were significantly higher than baseline by Dunnett's test (one-sided) (p < 0.05); the day 3 value was borderline statistically significant. These results show that phenytoin rapidly induces the activity of the CYP3A family of isozymes, with effects apparent within 48 h after the initiation of phenytoin therapy.