A mechanistic approach to antiepileptic drug interactions.
OBJECTIVE
To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach.


METHODS
A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts.


CONCLUSIONS
AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions.


CONCLUSIONS
By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.
Anderson
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Department of Pharmacy, School of Pharmacy, University of Washington, Seattle 98195, USA.
D000085:Acetates / Q000494:pharmacology; D000588:Amines; D000927:Anticonvulsants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D002220:Carbamazepine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005013:Ethosuximide / Q000494:pharmacology; D000078328:Felbamate; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D000077206:Gabapentin; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006801:Humans; D000077213:Lamotrigine; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009557:Nipecotic Acids / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D048448:Phenylcarbamates; D010672:Phenytoin / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D000078308:Tiagabine; D000077236:Topiramate; D014227:Triazines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D009557:Nipecotic Acids; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D005013:Ethosuximide; D014635:Valproic Acid; D010672:Phenytoin; D000077206:Gabapentin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D020888:Vigabatrin; D000077213:Lamotrigine; D000078328:Felbamate; D010634:Phenobarbital; D000078308:Tiagabine