The Influence of Dissolution, PMAT Influx, and MATE Efflux Rates on Paracellular Absorption of Metformin Using a Mechanistic Oral Absorption / PBPK Model

Authors: Bolger MB, Macwan J, Lukacova V
Conference: AAPS
Keywords: ACAT, ACAT model, Advanced Compartmental Absorption and Transit (ACAT™) model, dissolution rate, metformin, oral absorption, PBPK, PBPK modeling, transporters
Software: GastroPlus®
Division: PBPK

Purpose

A physiologically based absorption and distribution model was developed for metformin to facilitate our understanding of the influence of transporters and dissolution rate on oral absorption.

Methods

A mechanistic oral absorption ACAT / PBPK model for metformin was developed using GastroPlus™ (Simulations Plus, Inc., Lancaster CA). The model incorporated PMAT influx and MATE efflux transporters on the apical membrane of the intestinal lumen, along with paracellular permeability as the only route of absorption into the portal vein. Systemic clearance was modeled by using permeability-limited liver and kidney tissues with the following transporters: OCT1 (basolateral gut and liver influx), OCT2 (basolateral kidney influx), and MATE2K (apical kidney efflux). Transporter Km values were taken directly from in vitro literature studies and Vmax values were optimized to fit the observed clinical data. The model was validated by comparing the simulation results to literature data (Tucker 1981, Pentikainen 1979, and Balan 2001) for intravenous and oral administration assuming solution, IR, ER, and XR formulations of metformin administered to human subjects under fed and fasted conditions. The influence of dissolution rate on the rate and extent of metformin absorption was tested by using a variety of intestinal lumen metformin release rates using Weibull function profiles

2018 AAPS Workshop Drug Transporters in ADME: From the Bench to the Bedside, April 16-18, 2018, Herndon, VA

By Michael B. Bolger, Joyce Macwan, and Viera Lukacova