Interplay of Metabolism and Transport in Determining Oral Drug Absorption and Gut Wall Metabolism: A Simulation Assessment Using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” Model

Abstract

Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e.g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F(G)). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F(a)) and F(G) via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (Km) for CYP3A4 and P-gp (C(Lint-CYP3A4) and K(m-CYP3A4), CL(int-P-gp) and K(m-P-gp)). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F(G) whereas an increase in C(Lint-P-gp) resulted in a reduced F(a), but interestingly decreased F(G) too. The reduction in FG was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e.g. P(app), C(Lint-P-gp,) and K(m-P-gp)) and gut wall metabolism (e.g. C(Lint-CYP3A4,) K(m-CYP3A4)) resulted in disproportionate changes in F(G) compared to the magnitude of singular effects. The results suggest that P-gp efflux decre...

From preclinical to human – prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example

“…The free fraction of drug within the enterocyte is represented by the fu gut term. Detailed description of ADAM model can be found in the publication by Darwich et al [11].…”

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

“…There has been some movement in the field to accommodate a reduced or partial intestinal flow to the enterocyte region. 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).…”

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

“…The results demonstrated that accounting for the MDR1 distributions enhanced PBPK predictions of bioavailability for the development of the compound under study. Likewise, a study by Darwich and coworkers [56], which incorporated regional MDR1 and CYP3A expression into an ADAM model, demonstrated two points: non-uniform regional distribution of MDR1 in the small intestine and colon, and disparity between mRNA and protein expression. This highlights that protein and mRNA expression together with drug parameter data leads to successful capture of drug disposition.…”

“…Advanced models such as the advanced dissolution, absorption, and metabolism (ADAM) model and the advanced compartmental absorption and transit model (ACAT) are based on adaptations of the original compartmental absorption and transit (CAT) model which accounts for small intestinal transit time (SI), permeability, and radii. Most importantly, these advanced models incorporate gastrointestinal transporter-metabolism interplay [55,56]. A study by Bruyere and co-workers has highlighted the importance of obtaining regional intestinal transporter expression data for incorporation in PBPK models [57].…”