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

• Published in: Journal of pharmacy and pharmacology Vol. 56; no. 12; p. 1597
• Main Authors: Mizuma, Takashi, Tsuji, Akira, Hayashi, Masahiro
• Format: Journal Article
• Language: English
• Published: England 01.12.2004
• Subjects: Intestinal Absorption - drug effects; Intestinal Absorption - physiology; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Models, Biological; Pharmaceutical Preparations - metabolism
• ISSN: 0022-3573
• DOI: 10.1211/0022357044850

The pre-systemic intestinal extraction ratio (E(g)) 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 E(g) 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 E(g) of 0.228 was obtained according to the equation, F = F(f) x (1 - E(g)) x F(h), where F, F(f) and F(h) were the bioavailability, the fraction entering the intestinal tissue and the hepatic availability, respectively. Method 2: the E(g) 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 E(g) 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 E(g) 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.