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 C min ). 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 C min , C max , 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 21) is far slower than the clinical renal elimination rate constant (0.3 h 21 ). 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. IntroductionThe intrinsic rate and extent of blood cell partitioning of drugs can be reliably determined in a static in vitro system due to the absence of confounding processes present in vivo, including absorption, competing distribution to other tissues, and clearance (Hinderling, 1997). Although metformin is a first-line treatment of type 2 diabetes mellitus that has been commonly used for decades (Gong et al., 2012), its in vitro partitioning properties into the cellular component of blood have not been documented in the literature. Instead, erythrocytes are presumed to be an important distributional compartment for metformin based on the markedly longer blood versus plasma half-life in humans (Glucophage, 2009). Early clinical studies described metformin's in vivo blood-toplasma partition ratio (B/P) value as high (B/P . 10 at C min ), and partitioning as slow based on the apparent timedependent B/P, which increased over the duration of the dosing interval (Sirtori et al., 1978; Pentikainen et al., 1979;Tucker et al., 1981). Following oral administration of a single 1.5-g dose in humans, metformin B/P gradually increased from ,1 between 0 and 4 hours to .10 at 24 hours, with the B/P value becoming greater than unity at 4 hours (Tucker et al., 1981). More recent clinical studies demonstrated metformin elim...

Physiologically‐Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter–Mediated Interactions Between Metformin and Cimetidine

“…where X erythro and X plasma are the amount of metformin in the erythrocyte and plasma compartment, respectively, and k in,RBC and k out,RBC are the partitioning rate constants of metformin from plasma to erythrocytes and from erythrocytes to plasma, respectively, and obtained in vitro by measuring time‐dependent blood cell distribution of metformin using human blood ( Table ).…”

“…Metformin undergoes negligible hepatic metabolism, but it is mainly excreted intact into the urine; its renal clearance exceeds the glomerular filtration rate, indicating tubular secretion. With negligible plasma protein binding, metformin slowly distributes to erythrocytes . Metformin exists ionized at physiological pHs, relying on transporters for its translocation across cell membranes.…”

“…Physiologically‐based pharmacokinetic (PBPK) modeling analysis allows for quantitative prediction of drug concentration‐time profiles and enhances our mechanistic understanding of DDI . For metformin, a minimal PBPK model was previously reported but with no consideration of transporter‐mediated processes . Later, whole‐body PBPK models were developed with the mechanistic components reflecting transporter‐mediated processes (by OCT1, OCT2, and MATEs), namely, the conventional model and the “electrochemical model” driven by dynamically changing electrochemical modulation .…”

Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

“…Xie et al (2015) recently reported a PBPK model for metformin in which the incorporation of plasma -blood cell distribution rate constants allowed recovery of both plasma and whole blood drug concentrations over an extended time. When a blood cell distribution compartment was incorporated into the metformin PBPK model of the current study (using a similar approach to Xie et al), simulated plasma metformin concentrations and the extent of the DDI with cimetidine were unaffected (data not shown).…”

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations

“…Plasma binding of metformin is insignificant, so pregnancy‐induced alterations in plasma albumin levels are not expected to impact metformin disposition. However, metformin is a high extraction ratio compound in the kidney (Xie, Ke, Bowers, & Zamek‐Gliszczynski, ). Thus, pregnancy‐induced changes in metformin pharmacokinetics can be primarily attributed to increased renal blood flow, which increases both GFR and tubular secretion rate (Eyal et al, ), GFR is known to increase during the 1st trimester of pregnancy and to peak at mid‐pregnancy (↑37–45%), with a subsequent decrease in the last trimester (Tasnif et al, ).…”