Premium
Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.
Author(s) -
Riley RJ,
Kitteringham NR,
Park BK
Publication year - 1989
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 - 10.1111/j.1365-2125.1989.tb03530.x
Subject(s) - chemistry , epoxide hydrolase , pharmacology , microsomal epoxide hydrolase , in vitro , microsome , biochemistry , cytotoxic t cell , carbamazepine , toxicity , epoxide hydrolase 2 , enzyme , stereochemistry , biology , organic chemistry , neuroscience , epilepsy
The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism‐dependent toxicity of the latter is potentiated by pre‐treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase.