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Research ArticleArticle

Characterization of T-5 N-Oxide Formation as the First Highly Selective Measure of CYP3A5 Activity

Xiaohai Li, Valer Jeso, Scott Heyward, Gregory S. Walker, Raman Sharma, Glenn C. Micalizio and Michael D. Cameron
Drug Metabolism and Disposition March 2014, 42 (3) 334-342; DOI: https://doi.org/10.1124/dmd.113.054726
Xiaohai Li
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Valer Jeso
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Scott Heyward
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Gregory S. Walker
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Raman Sharma
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Glenn C. Micalizio
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Michael D. Cameron
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida (M.D.C., X.L.); Celsis In Vitro Technologies, Baltimore Maryland (S.H.); Department of Chemistry, Dartmouth College, Hanover, New Hampshire (V.J., G.C.M.), Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut (G.S.W., R.S.)
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Abstract

Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap, and there is currently no way to selectively monitor the activity of these two enzymes, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, with large individual differences in CYP3A5 expression level. The CYP3A5 genotype has been shown to alter the pharmacokinetics of drugs in clinical trials. We report the first tool compound capable of determining CYP3A5 activity in biologic samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N-oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N-oxide highly correlates with the CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.

Footnotes

    • Received September 3, 2013.
    • Accepted December 6, 2013.
  • This work was supported by a research grant from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R21 DK091630] (to M.D.C.).

  • dx.doi.org/10.1124/dmd.113.054726.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

Selective CYP3A5 Marker Reaction

Xiaohai Li, Valer Jeso, Scott Heyward, Gregory S. Walker, Raman Sharma, Glenn C. Micalizio and Michael D. Cameron
Drug Metabolism and Disposition March 1, 2014, 42 (3) 334-342; DOI: https://doi.org/10.1124/dmd.113.054726

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Research ArticleArticle

Selective CYP3A5 Marker Reaction

Xiaohai Li, Valer Jeso, Scott Heyward, Gregory S. Walker, Raman Sharma, Glenn C. Micalizio and Michael D. Cameron
Drug Metabolism and Disposition March 1, 2014, 42 (3) 334-342; DOI: https://doi.org/10.1124/dmd.113.054726
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