Abstract
Abstract 1 M. Bialer ( 1 Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel ) Antiepilpetic drugs (AEDs) can be categorized into three groups based on their potential to cause induction-drug interactions (DDI) with combined oral contraceptives (OC). The old AEDs such as phenobarbital, phenytoin and carbamazepine (CBZ) induce CYP-mediated metabolic pathways as well as glucuronide conjugation. Consequently, these enzyme-inducing AEDs reduce OC levels during concomitant administration and may cause contraceptive failure. A second group of AEDs includes topiramate (TPM), felbamate and oxcarbazepine (through its active monohydroxy metabolite or entity - licarbazepine), which are less potent inducers of CYP isozymes, but have been shown to alter OC plasma concentrations. A third group of AEDs includes valproic acid, gabapentin, lamotrigine (LTG), levetiracetam and tiagabine, which do not alter OC pharmacokinetics. A recent study evaluated the TPM-OC interaction in comparison to CBZ. Coadministration of TPM at daily doses of 50, 100, 200 mg did not have a statistical significant effect on the mean exposure or area under the curve AUC of ethinyl estradiol (−12%, +5% and −11%, respectively). A similar nonsignificant difference was observed with the norethindrone AUC and plasma levels (p > 0.05). In contrast to TPM, CBZ significantly decreased AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance (CL/F) by 69% and 127% (p < 0.05). These results show that in the above OC-DDI classification TPM should be categorized by the dose used. At daily doses below 200 mg, TPM belongs to the third group rather than the second one. Given the significant effect that CBZ coadministration (600 mg/day) had on the reduction of plasma levels and AUC values of norethindrone and ethinyl estradiol, it is clear that TPM does not cause a similar effect.Sabres et al. 2001 & 2003, showed that OC treatment reduces LTG plasma levels by more than 50%, which may require LTG dose adjustment. Withdrawal of OC may double LTG plasma levels. Reimers et al. 2005, demonstrated that it was the ethinyl estradiol component of the combined OC that interacted with LTG by inducing its metabolic glucuronide conjugation. Such an interaction might be expected with other AEDs that are metabolized primarily by glucuronidation mediated by the same glucuronide isozymes as LTG (e.g. UGT 1A4). In conclusion, DDI between AEDs and OC should indeed be looked at from both directions. On one side, both the estrogen and progestin complements of combined OC are very susceptible (sensitive) to enzyme inducation even by mild inducers such as OXC or TPM (>200 mg/day). On the other side, ethinyl estardiol as the estrogen component of combined OC may induce AEDs that are metabolized primarily by glucuronidation.
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