Measurement of in vivo microsomal epoxide hydrolase activity in white subjects.
An impairment or hereditary defect in microsomal epoxide hydrolase is considered a possible risk factor for drug and chemical toxicity. However, nothing is known about variability of in vivo epoxide hydrolase activity in humans. Our objectives were to develop and test a simple pharmacokinetic approach for measuring microsomal epoxide hydrolase activity in a population. After administration of carbamazepine-10,11-epoxide (100 mg), oral clearance showed a nearly linear relationship to the log (transdihydrodiol/epoxide) urine ratio in the 24- to 36-hour interval (log metabolic ratio). Intrasubject variability was assessed by administering the epoxide twice to 13 subjects (1- to 4-month interval); the log metabolic ratio did not change significantly (mean difference, 11%; paired t test, p = 0.79). In 110 healthy white adults, the log metabolic ratio ranged from 1.28 to 2.05 (mean +/- SD, 1.68 +/- 0.155). Outliers indicating enzyme-deficient phenotypes were not observed, and the frequency distribution was unimodal normal. The log metabolic ratio detected pronounced inhibition of epoxide hydrolase by valpromide (six subjects; median ratio, 0.91) and induction by phenobarbital/phenytoin (six subjects; median ratio, 2.42). We conclude that distribution of microsomal epoxide hydrolase activity in a study group can be measured pharmacokinetically by use of carbamazepine epoxide.
Kroetz
D L
DL
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Kerr
B M
BM
McFarland
L V
LV
Loiseau
P
P
Wilensky
A J
AJ
Levy
R H
RH
D000293:Adolescent; D000328:Adult; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D016011:Normal Distribution; D012016:Reference Values; D044465:White People
D002220:Carbamazepine; D004851:Epoxide Hydrolases; C012227:carbamazepine epoxide