Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent.
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.
Wang
R W
RW
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, USA. regina_wang@merck.com
Newton
D J
DJ
Liu
N
N
Atkins
W M
WM
Lu
A Y
AY
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008874:Midazolam / Q000378:metabolism / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D016593:Terfenadine / Q000378:metabolism / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
D011994:Recombinant Proteins; D013739:Testosterone; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine; D008874:Midazolam