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Research ArticleArticle

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Nina Isoherranen, Shana R. Ludington, Raymond C. Givens, Jatinder K. Lamba, Susan N. Pusek, E. Claire Dees, David K. Blough, Kazunori Iwanaga, Roy L. Hawke, Erin G. Schuetz, Paul B. Watkins, Kenneth E. Thummel and Mary F. Paine
Drug Metabolism and Disposition January 2008, 36 (1) 146-154; DOI: https://doi.org/10.1124/dmd.107.018382
Nina Isoherranen
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Shana R. Ludington
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Raymond C. Givens
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Jatinder K. Lamba
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Susan N. Pusek
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E. Claire Dees
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David K. Blough
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Kazunori Iwanaga
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Roy L. Hawke
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Erin G. Schuetz
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Paul B. Watkins
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Kenneth E. Thummel
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Mary F. Paine
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Abstract

Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5*1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5-HLM than in CYP3A5+ HLM with midazolam (Ki of 15 and 25 μM, respectively) but not with erythromycin (IC50 of 70 and 54 μM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (Ki of 7.7 and 54 μM, respectively) and erythromycin (IC50 of 100 and 350 μM, respectively). As predicted from HLM, with i.v. midazolam, the average (± S.D.) in vivo Ki (Ki,iv) was significantly higher in CYP3A5*1 carriers (24 ± 17 and 17 ± 8 μM for homozygous and heterozygous groups, respectively) than in noncarriers (13 ± 6 μM) (p = 0.02). With the erythromycin breath test, the average Ki,iv was not different between homozygous CYP3A5*1 carriers (30 ± 12 μM) and noncarriers (58 ± 53 μM). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.

Footnotes

  • This work was supported by the National Institutes of Health (M01 RR00046, R01 GM38149, R01 GM63666, P01 GM32165, U01 GM61393, and U01 GM61374).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.018382.

  • ABBREVIATIONS: HLM, human liver microsome(s); P-gp, P-glycoprotein; 1′-OH MDZ, 1′-hydroxymidazolam; rCYP3A, recombinant CYP3A; PBS-T, phosphate-buffered saline containing 0.3% Tween 20; Clint, intrinsic clearance; PCR, polymerase chain reaction; ERMBT, erythromycin breath test; HPLC, high-performance liquid chromatography; AUC, area under the plasma concentration versus time curve.

    • Received August 17, 2007.
    • Accepted October 19, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (1)
Drug Metabolism and Disposition
Vol. 36, Issue 1
1 Jan 2008
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Research ArticleArticle

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Nina Isoherranen, Shana R. Ludington, Raymond C. Givens, Jatinder K. Lamba, Susan N. Pusek, E. Claire Dees, David K. Blough, Kazunori Iwanaga, Roy L. Hawke, Erin G. Schuetz, Paul B. Watkins, Kenneth E. Thummel and Mary F. Paine
Drug Metabolism and Disposition January 1, 2008, 36 (1) 146-154; DOI: https://doi.org/10.1124/dmd.107.018382

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Research ArticleArticle

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Nina Isoherranen, Shana R. Ludington, Raymond C. Givens, Jatinder K. Lamba, Susan N. Pusek, E. Claire Dees, David K. Blough, Kazunori Iwanaga, Roy L. Hawke, Erin G. Schuetz, Paul B. Watkins, Kenneth E. Thummel and Mary F. Paine
Drug Metabolism and Disposition January 1, 2008, 36 (1) 146-154; DOI: https://doi.org/10.1124/dmd.107.018382
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