Abstract

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 (F_I) and, in turn, the systemic availability (F_sys) 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 (Q_Gut) 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 (f_Q), 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 Q_Gut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < Q_Gut model < TM in the description of F_I, 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 > Q_Gut model > TM. The findings suggest that the f_Q value strongly influences the rate of intestinal metabolism (F_I and F_sys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the f_Q value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.