Pharmacogenetics and drug interactions: role in antiepileptic-drug-induced teratogenesis.
Metabolism of antiepileptic drugs (AEDs) is a potentially major factor in AED-induced teratogenesis. When the parent compound is the teratogenic agent, pharmacogenetic variability in enzymatic metabolism and induction or inhibition of these enzymes by comedication are codeterminants of the teratogenic potential. When one of the parent compound's metabolites is the teratogenic agent, the balance between metabolic activation and detoxification is relevant to the teratogenic activity. Increased metabolic activation, decreased detoxification, or both will induce accumulation of the reactive metabolite. Genetic defects in detoxification pathways and the inhibition of these pathways by specific drug interactions probably have a greater impact on teratogenic risk than does high activity of metabolic activation. Insight into these factors involving AED metabolism might provide a rational basis for prevention by adjustment of medication, and in the future, for individual predictive testing for safest therapy.
Lindhout
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Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
D000014:Abnormalities, Drug-Induced / Q000235:genetics / Q000378:metabolism*; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology; D004198:Disease Susceptibility; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D010672:Phenytoin / Q000009:adverse effects / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*
D000927:Anticonvulsants; D010672:Phenytoin; D004851:Epoxide Hydrolases