Metformin Transport Rates Between Plasma and Red Blood Cells in Humans.

Area of Science:

• Pharmacokinetics
• Biophysics
• Computational Biology

Background:

• Metformin is a cornerstone therapy for type 2 diabetes, yet its precise mechanism of action and distribution dynamics remain incompletely understood.
• Existing hypotheses on metformin's movement between plasma and red blood cells (RBCs) lack definitive mechanistic explanation.

Purpose of the Study:

• To investigate the hypothesis that metformin distribution between plasma and RBCs is governed by concentration difference-driven passive transport.
• To quantify the transport rate coefficient for metformin between plasma and RBCs using in vivo data.

Main Methods:

• Utilized an ordinary differential equation (ODE) model with a two-compartment system to simulate passive diffusion between plasma and RBCs.
• Analyzed metformin concentration time series data from 35 individuals to parameterize the transport model.
• Approximated plasma metformin concentration decline using a biexponential function.

Main Results:

• A single passive transport coefficient (k = 0.044 ± 0.014 h⁻¹) effectively describes metformin uptake and release rates.
• The transport rate (v) is linearly proportional to the concentration difference between plasma (Mpl) and RBCs (M_RBC): v = k × (Mpl - M_RBC).

Conclusions:

• Passive transport driven by concentration gradients adequately explains metformin distribution dynamics between plasma and RBCs.
• This mechanism elucidates the rapid initial uptake into RBCs and subsequent faster release when plasma concentrations fall below RBC concentrations.