Induction of endogenous pathways by antiepileptics and clinical implications.
The aim of this study was to review modifications of the endogenous pathways (e.g. enzyme elevations, normal body constituent depletion or higher formation/excretion of endogenous metabolites) which could be ascribed to enzyme induction by antiepileptic drugs (AEDs). Information on older (e.g. phenobarbital, phenytoin and carbamazepine) and newer drugs (where information is available) is discussed together with clinical implications. The enzymes involved in the endogenous pathways and induced by the AEDs will not be limited to the hepatic microsomal enzymes; extrahepatic enzymes and/or enzymes present in other subcellular fractions will also be discussed, if pertinent. The induction of endogenous pathways by AEDs has been taken into account in the past, but much less emphasis has been given compared with the extensive literature on induction by AEDs of the metabolism of concomitantly administered drugs, either of the same or of different classes. Not all of the endogenous pathways examined and induced by AEDs appear to result in serious clinical consequences (e.g. induction of hepatic ALP, increased excretion of d-glucaric acid or of 6 beta-hydroxycortisol). In some cases, induction of some pathways (e.g. increase of high-density lipoprotein cholesterol or of conjugated bilirubin) might even be a beneficial side-effect, however enzyme induction is considered rather a detrimental aspect for an AED, as induction is generally a broad and a non-specific phenomenon. The new AEDs have generally less induction potential than the older agents. Yet some (felbamate, topiramate, oxcarbazepine and lamotrigine) have the potential for inducing enzymes, whereas others (levetiracetam, gabapentin and vigabatrin) appear to be completely devoid of enzyme inducing characteristics, at least as far as the enzymes investigated are concerned.
Strolin Benedetti
M
M
UCB Pharma S.A., Drug Metabolism and Pharmacokinetics, Nanterre, France. margheritastrolin@ucb-group.com
Ruty
B
B
Baltes
E
E
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000927:Anticonvulsants