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Research ArticleMetabolism, Transport, and Pharmacogenomics

Metformin's Intrinsic Blood-to-Plasma Partition Ratio (B/P): Reconciling the Perceived High In Vivo B/P > 10 with the In Vitro Equilibrium Value of Unity

Fang Xie, Alice B. Ke, Gary D. Bowers and Maciej J. Zamek-Gliszczynski
Journal of Pharmacology and Experimental Therapeutics August 2015, 354 (2) 225-229; DOI: https://doi.org/10.1124/jpet.115.225698
Fang Xie
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (F.X., G.D.B., M.J.Z.-G.); and Certara, Cary, North Carolina (A.B.K.)
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Alice B. Ke
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (F.X., G.D.B., M.J.Z.-G.); and Certara, Cary, North Carolina (A.B.K.)
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Gary D. Bowers
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (F.X., G.D.B., M.J.Z.-G.); and Certara, Cary, North Carolina (A.B.K.)
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Maciej J. Zamek-Gliszczynski
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (F.X., G.D.B., M.J.Z.-G.); and Certara, Cary, North Carolina (A.B.K.)
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Abstract

Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (>10 at Cmin). However, literature reports of metformin's intrinsic in vitro B/P values are lacking. At present, the extent and rate of metformin cellular partitioning was determined in incubations of fresh human and rat blood with [14C]metformin for up to 1 week at concentrations spanning steady-state plasma Cmin, Cmax, and a concentration associated with lactic acidosis. The results showed that metformin's intrinsic equilibrium B/P was ∼0.8–1.4 in blood, which is <10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and repartitioning back into plasma were slow (repartitioning half-life ∼32–39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio ∼90%–100%), explain why the clinical terminal half-life of metformin in plasma (6 hours) is 3- to 4-fold shorter than the half-life in whole blood (18 hours) and erythrocytes (23 hours). The rate constant for metformin repartitioning from blood cells to plasma (∼0.02 h−1) is far slower than the clinical renal elimination rate constant (0.3 h−1). Blood distributional rate constants were incorporated into a metformin physiologically-based pharmacokinetic model, which predicted the differential elimination half-life in plasma and blood. The present study demonstrates that the extent of cellular drug partitioning in blood observed in a dynamic in vivo system may be very different from the static in vitro values when repartitioning from blood cells is far slower than clearance of drug in plasma.

Footnotes

    • Received May 4, 2015.
    • Accepted June 9, 2015.
  • dx.doi.org/10.1124/jpet.115.225698.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 354 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 354, Issue 2
1 Aug 2015
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Metformin's Intrinsic Blood-to-Plasma Partition Ratio

Fang Xie, Alice B. Ke, Gary D. Bowers and Maciej J. Zamek-Gliszczynski
Journal of Pharmacology and Experimental Therapeutics August 1, 2015, 354 (2) 225-229; DOI: https://doi.org/10.1124/jpet.115.225698

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Metformin's Intrinsic Blood-to-Plasma Partition Ratio

Fang Xie, Alice B. Ke, Gary D. Bowers and Maciej J. Zamek-Gliszczynski
Journal of Pharmacology and Experimental Therapeutics August 1, 2015, 354 (2) 225-229; DOI: https://doi.org/10.1124/jpet.115.225698
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