Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent.

R W Wang, D J Newton, N Liu, W M Atkins, A Y Lu

Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, USA. regina_wang@merck.com

Drug metabolism and disposition: the biological fate of chemicals 2000 Mar

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Testosterone, terfenadine, midazolam, and nifedipine, four commonly used substrates for human cytochrome P-450 3A4 (CYP3A4), were studied in pairs in human liver microsomes and in microsomes from cells containing recombinant human CYP3A4 and P-450 reductase, to investigate in vitro substrate-substrate interaction with CYP3A4. The interaction patterns between compounds with CYP3A4 were found to be substrate-dependent. Mutual inhibition, partial inhibition, and activation were observed in the testosterone-terfenadine, testosterone-midazolam, or terfenadine-midazolam interactions. However, the most unusual result was the interaction between testosterone and nifedipine. Although nifedipine inhibited testosterone 6beta-hydroxylation in a concentration-dependent manner, testosterone did not inhibit nifedipine oxidation. Furthermore, the effect of testosterone and 7,8-benzoflavone on midazolam 1'-hydroxylation and 4-hydroxylation demonstrated different regiospecificities. These results may be explained by a model in which multiple substrates or ligands can bind concurrently to the active site of a single CYP3A4 molecule. However, the contribution of separate allosteric sites and conformational heterogeneity to the atypical kinetics of CYP3A4 can not be ruled out in this model.

Citation

R W Wang, D J Newton, N Liu, W M Atkins, A Y Lu. Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug metabolism and disposition: the biological fate of chemicals. 2000 Mar;28(3):360-6