P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

Abstract

ABSTRACT:Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16␣-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of

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

“…We have noted that heterogeneity models such as the SSFM and STM (Tam et al, 2003), whether necessary or not, are more pertinent in cases of enzyme heterogeneity among the segments. In absence of metabolism by the intestine, we found that the STM and SSFM perform as well as the TM and SFM, as found for studies on the absorption of benzoic acid (Cong et al, 2001) and digoxin absorption and efflux by P-gp (Liu et al, 2006) in the vascularly perfused intestine preparation. The presence of metabolite data is an absolute necessity for the discrimination between the SFM and TM.…”

“…2 for various drugs range from 2.4, 5.7, 8.6, to 16.6 l/h, corresponding to 6.5 to 43% of the total intestinal flow, with good predictions for midazolam but poor estimation of F I (or F G ) for saquinavir in vivo . Some of these f Q values for the Q Gut model are higher than the f Q values of 0.07, 0.024, and 0.2 estimated from fits of the SFM to the data on benzoic acid (Cong et al, 2001), morphine (Cong et al, 2000), and digoxin (Liu et al, 2006), respectively, from vascularly perfused rat small intestine preparations. For digoxin, which is mainly excreted unchanged in the mouse in vivo, a value of 0.16 was found for f Q (Chow et al, 2011).…”

“…Chow et al (2011) used the combined TM-PBPK and SFM-PBPK models to predict the 1.8-and 2.6-fold induction of brain and kidney P-glycoprotein (P-gp) protein expression with the vitamin D receptor ligand, 1␣,25-dihydroxyvitamin D 3 , respectively, and demonstrated a superior fit with the SFM-PBPK model in explaining the P-gp-mediated excretion of digoxin. In the perfused rat intestine preparation in which the intestine is the only eliminating tissue, the SFM was found to be superior to the TM in describing morphine glucuronidation (Cong et al, 2000) and digoxin excretion by the P-glycoprotein under induced and noninduced states (Liu et al, 2006). In this commentary, we appraised how these intestinal flow models differed by examining the effects of enterocytic flow on F I and, in turn, F sys and the extents of intestinal and liver first-pass removal with use of simulations.…”

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

“…The emergence of the Q Gut model (Yang et al, 2007) and the advanced dissolution, absorption, metabolism model from Simcyp (Darwich et al, 2010) favors this concept of partial flow. Other models that further encompass heterogeneity in transporters and enzymes have been adopted to explain the lesser intestinal metabolism observed for drugs given systemically versus orally (Tam et al, 2003;Liu et al, 2006;Bruyère et al, 2010;Gertz et al, 2010) as well as the effect of enterohepatic circulation of glucuronide conjugates (Wu, 2012). Undoubtedly, our PBPK investigation strongly supports the SFM for intestinal modeling.…”

Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum

“…It has been reported that the expression level and activity of P-450 isozymes are decreasing along with the length of the small intestine from the duodenum to the ileum (de Waziers et al, 1990;Liu et al, 2006). However, the distribution of CES isozyme has not been determined yet.…”