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Research ArticleArticle

Determination of Unbound Partition Coefficient and in Vitro–in Vivo Extrapolation for SLC13A Transporter–Mediated Uptake

Keith Riccardi, Zhenhong Li, Janice A. Brown, Matthew F. Gorgoglione, Mark Niosi, James Gosset, Kim Huard, Derek M. Erion and Li Di
Drug Metabolism and Disposition October 2016, 44 (10) 1633-1642; DOI: https://doi.org/10.1124/dmd.116.071837
Keith Riccardi
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Zhenhong Li
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Janice A. Brown
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Matthew F. Gorgoglione
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Mark Niosi
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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James Gosset
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Kim Huard
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Derek M. Erion
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Li Di
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT (K.R., J.A.B., M.N., L.D.); Cambridge, MA (M.F.G., J.G., K.H., D.M.E.)
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Abstract

Unbound partition coefficient (Kpuu) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. Kpuu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transporter-transfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher Kpuu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high Kpuu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different Kpuu values in human hepatocytes (Kpuu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. Kpuu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (Km) of SLC13A5 was estimated to be 24 μM for PF-06649298 in human hepatocytes. In vitro Kpuu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo Kpuu of liver-to-plasma, illustrating the potential of this approach to predict in vivo Kpuu from in vitro systems.

Footnotes

    • Received May 27, 2016.
    • Accepted July 13, 2016.
  • dx.doi.org/10.1124/dmd.116.071837.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticleArticle

Kpuu and IVIVE of SLC13A Transporter–Mediated Uptake

Keith Riccardi, Zhenhong Li, Janice A. Brown, Matthew F. Gorgoglione, Mark Niosi, James Gosset, Kim Huard, Derek M. Erion and Li Di
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1633-1642; DOI: https://doi.org/10.1124/dmd.116.071837

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Research ArticleArticle

Kpuu and IVIVE of SLC13A Transporter–Mediated Uptake

Keith Riccardi, Zhenhong Li, Janice A. Brown, Matthew F. Gorgoglione, Mark Niosi, James Gosset, Kim Huard, Derek M. Erion and Li Di
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1633-1642; DOI: https://doi.org/10.1124/dmd.116.071837
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