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Research ArticleArticle

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

Bhagwat Prasad, Raymond Evers, Anshul Gupta, Cornelis E. C. A. Hop, Laurent Salphati, Suneet Shukla, Suresh V. Ambudkar and Jashvant D. Unadkat
Drug Metabolism and Disposition January 2014, 42 (1) 78-88; DOI: https://doi.org/10.1124/dmd.113.053819
Bhagwat Prasad
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Raymond Evers
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Anshul Gupta
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Cornelis E. C. A. Hop
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Laurent Salphati
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Suneet Shukla
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Suresh V. Ambudkar
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Jashvant D. Unadkat
Department of Pharmaceutics, University of Washington, Seattle, Washington (B.P., J.D.U.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (R.E.); Drug Metabolism and Pharmacokinetics, Infection DMPK, AstraZeneca Pharmaceuticals LLP, Waltham, Massachusetts (A.G.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (C.E.H., L.S.); Laboratory of Cell Biology, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (S.S., S.V.A.)
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Abstract

Interindividual variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean ± S.D. (maximum/minimum range in parentheses) protein expression (fmol/µg of membrane protein) in human liver tissue was OATP1B1- 2.0 ± 0.9 (7), OATP1B3- 1.1 ± 0.5 (8), OATP2B1- 1 1.7 ± 0.6 (5), and P-gp- 0.4 ± 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to ∼40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and interindividual variability through physiologically based pharmacokinetic modeling.

Footnotes

    • Received July 22, 2013.
    • Accepted October 11, 2013.
  • R.E., A.G., C.E.H., and L.S. contributed equally to the research.

  • This study was supported by the University of Washington Research Affiliate Program on Transporters sponsored by AstraZeneca, Genentech, and Merck & Co., Inc. (http://sop.washington.edu/uwrapt). R.E. thanks the Merck Research Laboratories New Technologies Review and Licensing Committee for funding. A.G. thanks the AstraZeneca External Science Committee and licensing group for their support. S.S. and S.V.A were supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research (grant number ZIA BC010030-13).

  • dx.doi.org/10.1124.dmd.113.053819.

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

  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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Research ArticleArticle

Interindividual Variability in Hepatic Transporter Expression

Bhagwat Prasad, Raymond Evers, Anshul Gupta, Cornelis E. C. A. Hop, Laurent Salphati, Suneet Shukla, Suresh V. Ambudkar and Jashvant D. Unadkat
Drug Metabolism and Disposition January 1, 2014, 42 (1) 78-88; DOI: https://doi.org/10.1124/dmd.113.053819

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Research ArticleArticle

Interindividual Variability in Hepatic Transporter Expression

Bhagwat Prasad, Raymond Evers, Anshul Gupta, Cornelis E. C. A. Hop, Laurent Salphati, Suneet Shukla, Suresh V. Ambudkar and Jashvant D. Unadkat
Drug Metabolism and Disposition January 1, 2014, 42 (1) 78-88; DOI: https://doi.org/10.1124/dmd.113.053819
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