Quantitative prediction of in vivo drug interactions between nevirapine and antifungal agents from in vitro data in rats

We investigated the effects of ketoconazole (KCZ) and fluconazole (FCZ) on rat liver microsomal nevirapine (NVP) metabolism in vitro and on NVP plasma profiles in vivo in order to determine whether the in vivo drug interactio ns could be predicted quantitatively from the in vitro data. The K-i values of KCZ and FCZ for NVP 12-hydroxylation were 1.59 mu M and 11.5 mu M, resp ectively, indicating that KCZ inhibited this activity more strongly than FC Z in vitro, In contrast, FCZ orally pre-administered at 20 mg/kg to rats in creased the area under the plasma concentration-time curve (AUC) of NVP 7.4 -fold, whereas KCZ increased it 2.1-fold, compared to the vehicle. We next investigated the inhibitory potency and unbound concentrations of KCZ and F CZ in microsomal mixtures with or without rat albumin. In the presence of a lbumin, the inhibition by KCZ was greatly decreased. Further, the unbound f raction of KCZ was decreased dramatically to around 3%, whereas more than 9 0% of FCZ remained in unbound form, When the increase in the AUC for NVP wa s calculated based on the concentrations of unbound inhibitors in the porta l vein, good agreement with the observed in vivo values was obtained.