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.
J Pharmacol Exp Ther
; 354(2): 225-9, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-26062557
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 â¼0.8-1.4 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 â¼32-39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio â¼90%-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 (â¼0.02 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Plasma
/
Hipoglucemiantes
/
Metformina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
2015
Tipo del documento:
Article