Cytochrome P450 isozymes and antiepileptic drug interactions.

Article Details

Citation

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
DrugEnzymeKindOrganismPharmacological ActionActions
CarbamazepineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
FelbamateCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
PhenylbutazoneCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
PhenytoinCytochrome P450 2C19ProteinHumans
No
Substrate
Inducer
Details
PhenytoinCytochrome P450 2C9ProteinHumans
No
Substrate
Inhibitor
Inducer
Details