Metabolism of carbamazepine by CYP3A6: a model for in vitro drug interactions studies.
Carbamazepine (CBZ) is widely used in the treatment of epilepsy. The drug is principally metabolized by CYPs to 10, 11-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsant properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be implicated in CBZ biotransformation. Our purpose was to establish an experimental model to determine the interaction of CBZ with other antiepileptic drugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. We used liver microsomes from rabbit treated with various compounds known to induce principally some CYPs subfamilies. Having tested all the compounds we demonstrated that only the animals treated with CYP3A inducers were able to metabolize CBZ strongly. The CBZ biotransformation was inhibited by anti CYP3A antibodies. All the CYP3A subfamily substrates specifically decrease CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subfamily is primarily involved in CBZ metabolism. Using this model we investigated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, primidone, progabide, vigabatrin and lamotrigine.
Mesdjian
E
E
Centre Saint Paul et Laboratoire de Biologie Moléculaire appliquée au médicament, Marseille, France.
Sérée
E
E
Charvet
B
B
Mirrione
A
A
Bourgarel-Rey
V
V
Desobry
A
A
Barra
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002220:Carbamazepine / Q000378:metabolism* / Q000627:therapeutic use; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism / Q000494:pharmacology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011817:Rabbits
D000900:Anti-Bacterial Agents; D000906:Antibodies; D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D020033:Protein Isoforms; D002220:Carbamazepine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C100638:cytochrome P-450 CYP3A6 (rabbit); D009543:Nifedipine