Does the well-stirred model assess the intestinal first-pass effect well?

Abstract

The pre-systemic intestinal extraction ratio (Eg) has been estimated by an equation based on the well-stirred model, which does not have a term of membrane transport. In this report, we have identified the application limitations of the well-stirred model equation to assess the pre-systemic intestinal extraction ratio. The Eg of metoprolol (CYP2D6 substrate) was assessed by three methods. Intrinsic clearances for metoprolol metabolism in hepatic and gastrointestinal microsomes were from a published report. Method 1 (model-independent method): the Eg of 0.228 was obtained according to the equation, F = Ff × (1 — Eg) × Fh, where F, Ff and Fh were the bioavailability, the fraction entering the intestinal tissue and the hepatic availability, respectively. Method 2: the Eg of 0.0071 was calculated according to the well-stirred model equation, and was much lower than the value of 0.228. Method 3: the Eg of 0.213 was obtained by the transport-metabolism-flow (TMF) model equation, and was much closer to the value of 0.228 obtained by the model-independent method than the Eg of 0.0071 calculated by the well-stirred model equation. Therefore, we propose that the factor of membrane transport process be incorporated into the pharmacokinetic model for the assessment of the pre-systemic intestinal extraction ratio.