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

Abstract

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, ϳ0.05 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 firstpass 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.

Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo

“…With recognition that the intestine can significantly reduce the orally or intraduodenally absorbed dose during first-pass metabolism and that differential induction and inhibition patterns of the enzymes and transporters exist (see Pang and Chow, 2012;Chow and Pang, 2013), much effort is extended to separate the contributions of the intestine and liver in first-pass metabolism. The direct observations on intestinal metabolism could be deciphered for lorcainide metabolism in portacaval shunts in rodents (Gugler et al, 1975;Giacomini et al, 1980;Plänitz, et al, 1985) and midazolam oxidation in anhepatic patients after duodenal and intravenous administrations during transplant surgery (Paine et al, 1996).…”

“…Recent examination of intestinal flow models emphasized that the type of intestinal flow model chosen is important: TM, Q Gut model (Yang et al, 2007), or SFM, in which the fractional flow to enterocyte region (f Q ) is 1, 0.484, and 0.1-0.3, respectively (Pang and Chow, 2012). For most substrates, the fitted f Q is , 0.2 (Pang and Chow, 2012;Chow and Pang, 2013), and it is 0.10 for this study (Table 5).…”

“…Recent examination of intestinal flow models emphasized that the type of intestinal flow model chosen is important: TM, Q Gut model (Yang et al, 2007), or SFM, in which the fractional flow to enterocyte region (f Q ) is 1, 0.484, and 0.1-0.3, respectively (Pang and Chow, 2012). For most substrates, the fitted f Q is , 0.2 (Pang and Chow, 2012;Chow and Pang, 2013), and it is 0.10 for this study (Table 5). Since the percent contribution of the intestine during recirculation of M is dependent on f Q (see equations shown as footnotes to Table 7), we expect the ranking of SFM , Q Gut model , TM to stand, whereas the opposite exists for the percent contribution of liver (SFM .…”

“…The fractional contributions of the intestine and liver to the first-pass removal were estimated. The extents of intestine and liver removal of M are highly dependent on f Q , the fractional enterocyte flow (Pang and Chow, 2012) (eqs. 1 and 2): Obtained from Peters (2008), based on 60% of intestine volume.…”

“…In contrast, physiologically based pharmacokinetic (PBPK) models address events of sequential elimination and include transmembrane barriers Pang, 1986, 1993;Pang, 2003;Pang et al, 2009;Chow and Pang, 2013) and transporters (Sun et al, 2006. The intestine, richly endowed with enzymes and transporters (van Herwaarden et al, 2007;Zhang et al, 2007Zhang et al, , 2009Liu et al, 2010), strongly affects firstpass metabolism and controls the flow of substrate to the liver (Pang and Chow, 2012). Intestinally formed metabolites may undergo immediate sequential metabolism or excretion (Pang and Gillette, 1979).…”