Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.
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.
Riley
R J
RJ
Department of Pharmacology and Therapeutics, University of Liverpool.
Kitteringham
N R
NR
Park
B K
BK
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000378:metabolism; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology; D014508:Urea / Q000378:metabolism
D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D014508:Urea; D003577:Cytochrome P-450 Enzyme System