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Metformin Transport Rates Between Plasma and Red Blood Cells in Humans - PubMed

Metformin Transport Rates Between Plasma and Red Blood Cells in Humans

Janis Kurlovics et al. Clin Pharmacokinet. 2022 Jan.

Abstract

Background: Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs).

Objective: We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transport rate coefficient values based on metformin concentration time series in plasma and RBCs from in vivo studies.

Methods: An ordinary differential equation (ODE) system with two compartments was used to describe diffusion-based passive transport between plasma and RBCs. Metformin concentration time series in plasma and RBCs of 35 individuals were used for metformin transport parametrization. Plasma concentration has been approximated by biexponential decline.

Results: A single passive transport coefficient, k = 0.044 ± 0.014 (h-1), can be applied, describing the uptake and release transport rate versus the linear equation v = k × (Mpl - MRBC), where Mpl is the metformin concentration in plasma and MRBC is the metformin concentration in RBCs.

Conclusions: Our research suggests that passive transport can explain metformin distribution dynamics between plasma and RBCs because transport speed is proportional to the metformin concentration difference and independent of the transport direction. Concentration difference-driven passive transport can explain the mechanism of faster metformin distribution to RBCs the first few hours after administration, and faster release and domination of the redistribution transport rate after metformin concentration in plasma becomes smaller than in RBCs.

© 2021. The Author(s).

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Conflict of interest statement

Janis Kurlovics, Darta Maija Zake, Linda Zaharenko, Kristaps Berzins, Janis Klovins, and Egils Stalidzans have no conflicts of interest that are directly relevant to the contents of this article.

Figures

Fig. 1
Fig. 1

Two-compartment model of metformin transport between plasma and RBCs with absorption (vin) and release (vout) fluxes. kin transport rate coefficient to RBCs from plasma (h−1), kout transport rate coefficient from RBCs to plasma (h−1), Mpl metformin concentration in plasma (ng/mL), MRBC metformin concentration in RBCs (ng/mL), RBC red blood cells

Fig. 2
Fig. 2

Parameter estimation results of the average curve. Dots show experimental values while lines represent the model simulation. a Single k-value (kave = 0.044 h–1, mean square error = 286); and b independent kin and kout values (kin/ave = 0.044 and kout/ave = 0.039 h–1, mean square error = 273). RBCs red blood cells

Fig. 3
Fig. 3

Diffusion coefficient k, kin and kout values per individual (average values are represented by lines). The average values of k and kin were identical.

Fig. 4
Fig. 4

Tmax and Cmax of individual plasma curves. Tmax time to reach maximum concentration, Cmax maximum concentration

Fig. 5
Fig. 5

Parameter estimation results of the best-fit, individual 16. The dots show the experimental values, while the lines represent the model simulation. a Single k-value (k = 0.040, mean square error = 67); b different kin and kout values (kin = 0.040 and kout = 0.038, mean square error = 65)

Fig. 6
Fig. 6

Parameter estimation results of the worst-fit, individual 31. The dots show the experimental values, while the lines represent model simulation. a Single k-value (k = 0.058 h–1, mean square error = 9244); b different kin and kout values (kin = 0.055 h–1 and kout = 0.031 h–1, mean square error = 6271).

Fig. 7
Fig. 7

Dynamics of concentrations in a plasma and RBCs, and b influx (blue), outflux (red), and summary flux (green) to RBCs in the case of the average curve with a single coefficient. RBCs red blood cells

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