Blockade of P-Glycoprotein Decreased the Disposition of Phenformin and Increased Plasma Lactate Level

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration (2-75 µM) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was 1.9 µL/min while passive diffusion clearance was 0.31 µL/min. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as Cmax and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level.

Effect of increases in plasma lactate concentration on intravascular hemolysis during exhaustive exercise / 体力科学

A study was performed to examine the effect of plasma lactate concentration on intravascular hemolysis during exercise. Seven men performed maximal and submaximal exercise on a cycle ergometer. The maximal exercise was performed as a graded exercise until exhaustion. The mean performance time of the maximal exercise was 15 min and 4 s. The submaximal exercise was performed for 30 min at 50% HRmax. Blood samples were obtained before, immediately after, and one hour after exercise. Plasma lactate concentration, hematocrit (Ht), and serum haptoglobin concentration (Hp) were measured. Hp was corrected by Ht for hemoconcentration and expressed as HpC. Plasma lactate concentration was elevated significantly (p<0.05) immediately after maximal exercise, and returned to the baseline values one hour after exercise, whereas plasma lactate concentration did not change after submaximal exercise. Hp and HpC did not change even after maximal exercise. These results suggest that the elevation in plasma lactate concentration may not affect intravascular hemolysis during exercise.