Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy.
1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]-cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta-hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11-epoxide and trans-dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta-hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans-dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose-levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min-1 mg-1 protein) than in drug-free controls (23.4 pmol diol min-1 mg-1 protein (95% CI for difference -9 to -0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.
Pirmohamed
M
M
Department of Pharmacology and Therapeutics, University of Liverpool.
Allott
R
R
Green
V J
VJ
Kitteringham
N R
NR
Chadwick
D
D
Park
B K
BK
D000293:Adolescent; D000328:Adult; D000368:Aged; D002220:Carbamazepine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000187:drug effects*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged
D002220:Carbamazepine; D004851:Epoxide Hydrolases