Received for publication September 30, 2004.
Revised November 18, 2004.
Accepted for publication November 24, 2004.

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

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-epoxide formation can be associated with the clinical drug interaction between felbatame and carbamazepine (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 pontently increases carbamazepine-epoxide (CBZ-ep) formation by a maximum of 500 % at 300µM. Testosterone and progesterone activates by a maximum of 1680% and 920% respectively at 150µM and quinidine causes a 130% increase at 300µM. The predicted maximum in vivo decrease in steady state concentration of carbamazepine (CssCBZ) at saturating effector concentrations is 85-90% 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 CssCBZ change is predicted to 20% for testosterone, artemisinin and quinidine and 10% for progesterone, with a concomitant Css_CBZ-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 predicitivity is high and heteroactivation of an external test-set correlate to observed in vitro heteroactivation.

Key words: CYP3A4, drug drug interactions, enzyme kinetics, heteroactivation, in vitro - in vivo scaling, pharmacophore

This article has been cited by other articles:

				E. M. Isin and F. P. Guengerich Kinetics and Thermodynamics of Ligand Binding by Cytochrome P450 3A4 J. Biol. Chem., April 7, 2006; 281(14): 9127 - 9136. [Abstract] [Full Text] [PDF]