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 i s principally metabolized by CYPs to 10, Il-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsa nt properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be i mplicated in CBZ biotransformation. Our purpose was to establish an experim ental model to determine the interaction of CBZ with other antiepileptic dr ugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. W e 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 ant i CYP3A antibodies. All the CYP3A subfamily substrates specifically decreas e CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subf amily is primarily involved in CBZ metabolism. Using this model we investig ated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, p rimidone, progabide, vigabatrin and lamotrigine.