Cytochrome P450 isozymes and antiepileptic drug interactions.
Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phenytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition-based interactions possible. PHT is eliminated principally by hydroxylation to p-HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S-mephenytoin hydroxylase). The principle of isoform specificity (drugs metabolized by the same isoform should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S-warfarin and tolbutamide. Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9. The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19. For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ-10, 11-epoxide. This explains the pronounced interactions of CBZ with erythromycin, troleandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin). Work is in progress to explain the interactions of CBZ with other inhibitors. The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.
Levy
R H
RH
Department of Pharmaceutics, University of Washington, Seattle 98195-7610, USA.
D001189:Aryl Hydrocarbon Hydroxylases; D002220:Carbamazepine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010672:Phenytoin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D002220:Carbamazepine; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating