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.
Fleishaker
J C
JC
Clinical Pharmacokinetics Units, Upjohn Company, Kalamazoo, MI 49007, USA.
Pearson
L K
LK
Peters
G R
GR
D000293:Adolescent; D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D007527:Isoenzymes; D008297:Male; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
D007527:Isoenzymes; C001380:6 beta-hydroxycortisol; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006854:Hydrocortisone