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The mechanism of the carbamazepine-valproate interaction in humans.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 1997 Jul; Vol. 44 (1), pp. 21-7. - Publication Year :
- 1997
-
Abstract
- Aims: The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine-10,11-epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol.<br />Methods: Clearances of plasma carbamazepine, carbamazepine-epoxide and carbamazepine-diol to relevant carbamazepine metabolites present in urine were measured under steady-state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate.<br />Results: Plasma carbamazepine-epoxide concentrations were higher, relative to carbamazepine dose, in the co-medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine-10,11-trans-diol conjugate, and probably of carbamazepine-10,11-trans-diol, were lower in subjects co-medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine-10,11-epoxide.<br />Conclusions: Valproate appears to inhibit the glucuronidation of carbamazepine-10,11-trans-diol, and probably also inhibits the conversion of carbamazepine-10,11-epoxide to this trans-diol derivative, rather than simply inhibiting the latter reaction only.
- Subjects :
- Adult
Anticonvulsants administration & dosage
Anticonvulsants therapeutic use
Carbamazepine administration & dosage
Carbamazepine analogs & derivatives
Carbamazepine blood
Carbamazepine therapeutic use
Carbamazepine urine
Drug Therapy, Combination
Epilepsy blood
Epilepsy drug therapy
Epilepsy urine
Female
Humans
Male
Middle Aged
Valproic Acid administration & dosage
Valproic Acid therapeutic use
Anticonvulsants pharmacokinetics
Anticonvulsants pharmacology
Carbamazepine pharmacokinetics
Epilepsy metabolism
Valproic Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0306-5251
- Volume :
- 44
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9241092
- Full Text :
- https://doi.org/10.1046/j.1365-2125.1997.00607.x