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Research ArticleArticle

Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban

Donglu Zhang, Kan He, John J. Herbst, Janet Kolb, Wilson Shou, Lifei Wang, Praveen V. Balimane, Yong-Hae Han, Jinping Gan, Charles E. Frost and W. Griffith Humphreys
Drug Metabolism and Disposition April 2013, 41 (4) 827-835; DOI: https://doi.org/10.1124/dmd.112.050260
Donglu Zhang
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Kan He
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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John J. Herbst
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Janet Kolb
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Wilson Shou
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Lifei Wang
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Praveen V. Balimane
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Yong-Hae Han
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Jinping Gan
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Charles E. Frost
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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W. Griffith Humphreys
Pharmaceutical Candidate Optimization (D.Z., K.H., L.W., P.B., Y.-H.H., J.G., W.G.H.), Discovery Medicine and Clinical Pharmacology (C.E.F.), Bristol-Myers Squibb, Princeton, New Jersey; and Lead Profiling (J.J.H., J.K., W.S.), Bristol-Myers Squibb, Wallingford, Connecticut
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Abstract

The studies reported here were conducted to investigate the transport characteristics of apixaban (1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) and to understand the impact of transporters on apixaban distribution and disposition. In human permeability glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-cDNA–transfected cell monolayers as well as Caco-2 cell monolayers, the apparent efflux ratio of basolateral-to-apical (PcB-A) versus apical-to-basolateral permeability (PcA-B) of apixaban was >10. The P-gp- and BCRP-facilitated transport of apixaban was concentration- and time-dependent and did not show saturation over a wide range of concentrations (1–100 μM). The efflux transport of apixaban was also demonstrated by the lower mucosal-to-serosal permeability than that of the serosal-to-mucosal direction in isolated rat jejunum segments. Apixaban did not inhibit digoxin transport in Caco-2 cells. Ketoconazole decreased the P-gp-mediated apixaban efflux in Caco-2 and the P-gp-cDNA–transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in the BCRP-cDNA–transfected cell monolayers. Coincubation of a P-gp inhibitor (ketoconazole or cyclosporin A) and a BCRP inhibitor (Ko134) provided more complete inhibition of apixaban efflux in Caco-2 cells than separate inhibition by individual inhibitors. Naproxen inhibited apixaban efflux in Caco-2 cells but showed only a minimal effect on apixaban transport in the BCRP-transfected cells. Naproxen was the first nonsteroidal antiinflammatory drug that was demonstrated as a weak P-gp inhibitor. These results demonstrate that apixaban is a substrate for efflux transporters P-gp and BCRP, which can help explain its low brain penetration, and low fetal exposures and high milk excretion in rats.

Footnotes

  • dx.doi.org/10.1124/dmd.112.050260.

  • Received November 2, 2012.
  • Accepted January 28, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (4)
Drug Metabolism and Disposition
Vol. 41, Issue 4
1 Apr 2013
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Research ArticleArticle

Efflux Transporters in Apixaban Disposition

Donglu Zhang, Kan He, John J. Herbst, Janet Kolb, Wilson Shou, Lifei Wang, Praveen V. Balimane, Yong-Hae Han, Jinping Gan, Charles E. Frost and W. Griffith Humphreys
Drug Metabolism and Disposition April 1, 2013, 41 (4) 827-835; DOI: https://doi.org/10.1124/dmd.112.050260

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Research ArticleArticle

Efflux Transporters in Apixaban Disposition

Donglu Zhang, Kan He, John J. Herbst, Janet Kolb, Wilson Shou, Lifei Wang, Praveen V. Balimane, Yong-Hae Han, Jinping Gan, Charles E. Frost and W. Griffith Humphreys
Drug Metabolism and Disposition April 1, 2013, 41 (4) 827-835; DOI: https://doi.org/10.1124/dmd.112.050260
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