Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGut Model

Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the intestinal availability (FI) and, in turn, the systemic availability (Fsys) and intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (QGut) model stipulate that 1.0, ∼0.05 to 0.3, and ≤0.484× of the total intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (fQ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the QGut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < QGut model < TM in the description of FI, and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to first-pass removal was the opposite: SFM > QGut model > TM. The findings suggest that the fQ value strongly influences the rate of intestinal metabolism (FI and Fsys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the fQ value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.