PRIMARY HUMAN HEPATOCYTES AS A TOOL FOR THE EVALUATION OF STRUCTURE-ACTIVITY RELATIONSHIP IN CYTOCHROME-P450 INDUCTION POTENTIAL OF XENOBIOTICS - EVALUATION OF RIFAMPIN, RIFAPENTINE AND RIFABUTIN

In our laboratory, primary human hepatocytes are being investigated as an in vitro experimental system for the evaluation of pharmacokinetic drug-drug interactions. Our study here represents the first reported study that directly compares the cytochrome P450 isozyme 3A (CYP3A) in duction potential of three antimicrobials derived from rifamycin B, na mely, rifampin, rifapentine and rifabutin. Two endpoints of CYP3A acti vity, testosterone 6 beta-hydroxylation and midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from four different human donors show consistently that rifampin and rifapentine are poten t inducers of CYP3A, while a significantly lower induction potential i s observed for rifabutin. The relative induction potency of the three antimicrobials (rifampin > rifapentine much greater than rifabutin) is consistent with the available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase activity, CYP2C8/9 measured as tolbuta mide 4-hydroxylation activity, CYP2D6 measured as dextromethorphan O-d emethylation, and AZT glucuronidation, there is either no effect or! w here induction is found to be statistically significant in these other endpoints, the maximum induction values are consistently < 100% of th e control. Our results suggest that CYP3A is the major CYP induced by these rifamycin B derivatives. These studies illustrate the applicatio n of human hepatocytes in the evaluation of the structure-activity rel ationships in CYP induction for this class of chemicals and as an in v itro screen for drug-drug interaction potential via CTP induction. (C) 1997 Elsevier Science Ireland Ltd.