title: 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.
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 [(14)C]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.
authors.affiliation: 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.).
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: 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.).
authors.forename: Alice B
authors.initials: AB
authors.lastname: Ke
authors.affiliation: 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.).
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bowers
authors.affiliation: 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.) maciej.x.zamek-gliszczynski@gsk.com.
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
mesh_terms: D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000097:blood* / Q000494:pharmacology; D010949:Plasma / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin