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The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans

Patrick J. Roberts, Kristan D. Rollins, Angela D. M. Kashuba, Mary F. Paine, Andrew C. Nelsen, Eric E. Williams, Cassandra Moran, Jatinder K. Lamba, Erin G. Schuetz and Roy L. Hawke
Drug Metabolism and Disposition August 2008, 36 (8) 1465-1469; DOI: https://doi.org/10.1124/dmd.107.020065
Patrick J. Roberts
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Kristan D. Rollins
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Angela D. M. Kashuba
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Mary F. Paine
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Andrew C. Nelsen
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Eric E. Williams
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Cassandra Moran
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Jatinder K. Lamba
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Erin G. Schuetz
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Roy L. Hawke
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Abstract

The CYP3A5*1 allele has been associated with differences in the metabolism of some CYP3A substrates. CYP3A5 polymorphism may also influence susceptibility for certain drug interactions. We have previously noted a correlation between basal CYP3A activity and the inductive effects of dexamethasone using the erythromycin breath test (ERBT). To determine whether CYP3A5 polymorphism influences induction of CYP3A activity, we examined the effect of an antiemetic regimen of dexamethasone, and the prototypical inducer rifampin, on the ERBT in African American volunteers prospectively stratified by CYP3A5*1 allele carrier status. Mean basal ERBTs were significantly higher in CYP3A5*1 carriers (2.71 ± 0.53%) versus noncarriers (2.12 ± 0.37%, P = 0.006). Rifampin increased ERBTs in CYP3A5*1 carriers (4.68 versus 2.60%, P = 0.0008) and noncarriers (3.55 versus 2.11%, P = 0.0017), whereas dexamethasone increased ERBTs only in CYP3A5*1 noncarriers (3.03 versus 2.14%, P = 0.031). CYP3A5 polymorphism appears to influence susceptibility to induction-type drug interactions for some inducers, and CYP3A5*1 noncarriers may be more susceptible to the inductive effects of dexamethasone as a result of lower basal CYP3A activity.

Footnotes

  • This work was supported through grants from the General Clinical Research Centers program of the Division of Research Resources (RR00046), National Institutes of Health, a Center on Minority Aging Award from the University of North Carolina Institute on Aging (R.L.H.), National Institute of Child Health and Human Development 5U10 HD045962-03 (C.M.), and from National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org) under Grant U01 GM61393.

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

  • doi:10.1124/dmd.107.020065.

  • ABBREVIATIONS: ERBT, erythromycin breath test; LD, linkage disequilibrium; PXR, pregnane X receptor.

    • Received December 9, 2007.
    • Accepted May 16, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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OtherShort Communication

The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans

Patrick J. Roberts, Kristan D. Rollins, Angela D. M. Kashuba, Mary F. Paine, Andrew C. Nelsen, Eric E. Williams, Cassandra Moran, Jatinder K. Lamba, Erin G. Schuetz and Roy L. Hawke
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1465-1469; DOI: https://doi.org/10.1124/dmd.107.020065

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OtherShort Communication

The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans

Patrick J. Roberts, Kristan D. Rollins, Angela D. M. Kashuba, Mary F. Paine, Andrew C. Nelsen, Eric E. Williams, Cassandra Moran, Jatinder K. Lamba, Erin G. Schuetz and Roy L. Hawke
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1465-1469; DOI: https://doi.org/10.1124/dmd.107.020065
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