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The mechanism of the carbamazepine‐valproate interaction in humans
Author(s) -
Bernus I.,
Dickinson R. G.,
Hooper W. D.,
Eadie M. J.
Publication year - 1997
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1997.00607.x
Subject(s) - carbamazepine , chemistry , anticonvulsant , pharmacology , epoxide , epilepsy , medicine , biochemistry , psychiatry , catalysis
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. 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. 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. 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.