title: Quantitative prediction of in vivo profiles of CYP3A4 induction in humans from in vitro results with a reporter gene assay.
abstract: 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 (R(in vivo)) caused by prototypical inducers based on the alterations in the hepatic intrinsic clearance of probe drugs. Next, we derived equations by which these R(in 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 R(in 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.
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Kozawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Honma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D001709:Biotechnology / Q000379:methods*; D051544:Cytochrome P-450 CYP3A / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008432:Mathematical Computing; D010634:Phenobarbital / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin; D010634:Phenobarbital