ISSN:
1573-6822
Keywords:
drug development
;
drug interactions
;
drug metabolism
;
drug toxicity
;
human hepatocytes
;
pharmacokinetics
;
rifampin
;
terfenadine
Source:
Springer Online Journal Archives 1860-2000
Topics:
Biology
,
Medicine
Notes:
Abstract The utility of primary human hepatocytes in the evaluation of drug-drug interactions is being investigated in our laboratories. Our initial approach was to investigate whether drug-drug interactions observed in humans in vivo could be reproduced in vitro using human hepatocytes. Two model drugs were studied: terfenadine and rifampin, representing compounds subjected to drug-drug interactions via inhibitory and induction mechanisms, respectively. Terfenadine was found to be metabolized by human hepatocytes to C-oxidation and N-dealkylation products as observed in humans in vivo. Metabolism by human hepatocytes was found to be inhibited by drugs which are known to be inhibitory in vivo, Ki values for the various inhibitors were derived from the in vitro metabolism data, resulting in the following ranking of inhibitory potency: For the inhibition of C-oxidation, ketoconazole 〉 itraconazole 〉 cyclosporin ~ troleandomycin 〉 erythromycin 〉 naringenin. For the inhibition of N-dealkylation, itraconazole ≥ ketoconazole 〉 cyclosporin ≥ naringenin ≥ erythromycin ≥ troleandomycin. Rifampin induction of CYP3A, a known effect of rifampin in vivo, was also reproduced in primary human hepatocytes. Induction of CYP3A4, measured as testosterone 6β-hydroxylation, was found to be dose-dependent, treatment duration-dependent, and reversible. The induction effect of rifampin was observed in hepatocytes isolated from all 7 human donors studied, with ages ranging from 1.7 to 78 years. To demonstrate that the rifampin-induction of testosterone 6β-hydroxylation could be generalized to other CYP3A4 substrates, we evaluated the metabolism of another known substrate of CYP3A4, lidocaine. Dose-dependent induction of lidocaine metabolism by rifampin is observed. Our results suggest that primary human hepatocytes may be a useful experimental system for preclinical evaluation of drug-drug interaction potential during drug development, and as a tool to evaluate the mechanism of clinically observed drug-drug interactions.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007451911843
