Abstract
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 μM. Testosterone and progesterone activates by a maximum of 1680 and 920%, respectively, at 150 μM, and quinidine causes a 130% increase at 300 μM. The predicted maximum in vivo decrease in steady-state concentration of carbamazepine (CssCBZ) 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 CssCBZ-ep is 50, 60, 55, and 30% for artemisinin, testosterone, progesterone, and quinidine, respectively. At effector concentrations relevant in vivo, the CssCBZ change is predicted to ≤20% for testosterone, artemisinin, and quinidine and ≤10% for progesterone, with a concomitant CssCBZ-ep increase of 12% for testosterone and ≤10% 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.
Footnotes
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doi:10.1124/jpet.104.078519.
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ABBREVIATIONS: ep, epoxide; DMF, dimethylformamide; HPLC, high-pressure liquid chromatography; HLM, human liver microsome; MeOH, methanol; CssCBZ, plasma steady-state concentration of carbamazepine; CssCBZ-ep, plasma steady-state concentration of carbamazepine-ep; v150%, concentration of heteroactivator giving 150% of reaction velocity; %act, percent activation caused by 100 μM effector and 100 μM carbamazepine.
- Received September 29, 2004.
- Accepted November 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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