RT Journal Article
SR Electronic
T1 Prediction of Flow Effects on Intestinal (F<sub>I</sub>) and Systemic Availability (F<sub>sys</sub>) in PBPK Intestine Models: The Traditional Model (TM), Segregated Flow Model (SFM) and Q<sub>Gut</sub> Model
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.045872
DO 10.1124/dmd.112.045872
A1 K. Sandy Pang
A1 Edwin C. Y. Chow
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/06/27/dmd.112.045872.abstract
AB 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 (FI) and in turn, the systemic availability (Fsys) 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 QGut 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, 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-physiological-based pharmacokinetic (PBPK) models, showed the ranking was SFM &lt; QGut model &lt; TM in the description of FI, 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 &gt; QGut model &gt; 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 model poses serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.