Cytochrome P450 isozymes and antiepileptic drug interactions.
Article Details
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Levy RH
Cytochrome P450 isozymes and antiepileptic drug interactions.
Epilepsia. 1995;36 Suppl 5:S8-13.
- PubMed ID
- 8806399 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Carbamazepine Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Felbamate Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Phenylbutazone Cytochrome P450 2C9 Protein Humans UnknownSubstrateInhibitorDetails Phenytoin Cytochrome P450 2C19 Protein Humans NoSubstrateInducerDetails Phenytoin Cytochrome P450 2C9 Protein Humans NoSubstrateInhibitorInducerDetails