Predictive models of CYP3A4 heteroactivation: In vitro-in vivo scaling and pharmacophore modeling

Although activation of CYP3A4 is frequently observed in vitro, predictive computational-based models and methods for in vitro-in vivo scaling are scarce. It has been previously shown that in vitro CYP3A4 heteroactivation of carbamazepine (CBZ)-epoxide (ep) formation can be associated with the clinical drug interaction between felbatame and CBZ. The previously reported prediction methodology is applied here to an additional set of in vitro CYP3A4 heteroactivators, some exerting this effect at concentrations relevant in vivo. The antimalarial artemisinin potently increases CBZ-ep formation by a maximum of 500% at 300 muM. Testosterone and progesterone activates by a maximum of 1680 and 920%, respectively, at 150 muM, and quinidine causes a 130% increase at 300 muM. The predicted maximum in vivo decrease in steady-state concentration of carbamazepine (Css(CBZ)) at saturating effector concentrations is 85 to 90% for testosterone and progesterone, 75% for artemisinin, and 45% for quinidine. The corresponding predicted in vivo increase in Css(CBZ-ep) is 50, 60, 55, and 30% for artemisinin, testosterone, progesterone, and quinidine, respectively. At effector concentrations relevant in vivo, the Css(CBZ) change is predicted to less than or equal to20% for testosterone, artemisinin, and quinidine and less than or equal to10% for progesterone, with a concomitant Css(CBZ-ep) increase of 12% for testosterone and less than or equal to10% for progesterone, artemisinin, and quinidine. Structure-heteroactivation relationships were evaluated by generating a pharmacophore. The model includes two hydrogen bond acceptor features separated by hydrophobic features. Internal predictivity is high, and heteroactivation of an external test set correlate to observed in vitro heteroactivation.