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Research ArticleArticle

Human Cytochrome P-450 3A4: In Vitro Drug-Drug Interaction Patterns Are Substrate-Dependent

Regina W. Wang, Deborah J. Newton, Nini Liu, William M. Atkins and Anthony Y. H. Lu
Drug Metabolism and Disposition March 2000, 28 (3) 360-366;
Regina W. Wang
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Deborah J. Newton
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Nini Liu
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William M. Atkins
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Anthony Y. H. Lu
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Abstract

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 6β-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.

Footnotes

  • Send reprint requests to: Regina W. Wang, Department of Drug Metabolism, RY80-D100, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. E-mail: regina_wang{at}merck.com

  • ↵1 Parts of this work were presented at 11th International Conference on Cytochrome P450 in Sendai, Japan.

  • ↵2 Current address: Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.

  • Abbreviations used are::
    CYP3A4
    human cytochrome P-450 3A4
    CYP3A4/OR
    cytochrome P-450 3A4 and NADPH-cytochrome P-450 reductase
    • Received July 27, 1999.
    • Accepted November 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (3)
Drug Metabolism and Disposition
Vol. 28, Issue 3
1 Mar 2000
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Research ArticleArticle

Human Cytochrome P-450 3A4: In Vitro Drug-Drug Interaction Patterns Are Substrate-Dependent

Regina W. Wang, Deborah J. Newton, Nini Liu, William M. Atkins and Anthony Y. H. Lu
Drug Metabolism and Disposition March 1, 2000, 28 (3) 360-366;

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Research ArticleArticle

Human Cytochrome P-450 3A4: In Vitro Drug-Drug Interaction Patterns Are Substrate-Dependent

Regina W. Wang, Deborah J. Newton, Nini Liu, William M. Atkins and Anthony Y. H. Lu
Drug Metabolism and Disposition March 1, 2000, 28 (3) 360-366;
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