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 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 one week at concentrations spanning steady-state plasma Cmin, Cmax, and a concentration associated with lactic acidosis. The results showed that metfomin intrinsic equilibrium B/P was approximately 0.8-1.4 in blood, which is <10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and re-partitioning back into plasma were slow (re-partitioning half-life ~32-39 h). 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 h) is 3-4-fold shorter than half-life in whole blood (18 h) and erythrocytes (23 h). The rate constant for metformin re-partitioning from blood cells to plasma (0.02 h-1) is far slower than clinical renal elimination rate constant (0.3 h-1). Blood distributional rate constants were incorporated into a metformin PBPK 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 re-partitioning from blood cells is far slower than clearance of drug in plasma.
- The American Society for Pharmacology and Experimental Therapeutics