Quantitative Prediction of in Vivo Profiles of CYP3A4 Induction in Humans from in Vitro Results with a Reporter Gene Assay

Although primary human hepatocytes are commonly used for induction studies, the evaluation method is associated with several problems. More recently, a reporter gene assay has been suggested to be an alternative, although the contribution of only transfected nuclear receptors can be evaluated. The aim of the present study was to establish a method by which the extent of in vivo CYP3A4 induction in humans can be quantitatively predicted based on in vitro results with a reporter gene assay. From previous reports, we calculated in vivo induction ratios (Rin vivo) caused by prototypical inducers based on the alterations in the hepatic intrinsic clearance of probe drugs. Next, we derived equations by which these Rin vivo values can be predicted from the results of a reporter gene assay. To use the data obtained from a reporter gene assay, rifampicin was used as a reference drug. The correction coefficient (CC), which is used to quantitatively correlate the activity of inducers between in vitro and in vivo situations, was calculated by comparing the predicted data with the observed R-in (vivo) values for rifampicin. With the calculated CC value, good correlations were found between the predicted and observed Rin vivo values for other inducers such as phenobarbital, phenytoin, and omeprazole. Taken together, with the equations derived in the present study, we have been able to predict the extent of in vivo induction of human CYP3A4 by inducers in a time-dependent and quantitative manner from in vitro data.