Abstract

PBPK models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited in the appraisal of flow effects on the intestinal availability (F_I) and in turn, the systemic availability (F_sys) and intestinal vs. liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), the segregated flow model (SFM) and the Q_Gut model, respectively, stipulate that 1.0x, ~0.1x to 0.3x and 0.484x of the total intestinal flow reach the enterocyte region which 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-physiological-based pharmacokinetic (PBPK) models, showed the ranking was 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. But the ranking for the predicted contribution of hepatic metabolism to first-pass removal was 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 model poses serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.