Mechanistic Approaches to Predicting Oral Drug Absorption

Abstract

Abstract. Modeling and simulation of oral drug absorption have been widely used in drug discovery, development, and regulation. Predictive absorption models are used to determine the rate and extent of oral drug absorption, facilitate lead drug candidate selection, establish formulation development strategy, and support the development of regulatory policies. This review highlights the development of recent drug absorption models including dispersion and compartmental models. The compartmental models include the compartmental absorption and transit model; Grass model; gastrointestinal transit absorption model; advanced compartmental absorption and transit model; and advanced dissolution, absorption, and metabolism model. Compared to the early absorption models, the above models developed or extended since the mid-1990s have demonstrated greatly improved predictive performance by accounting for multiple factors such as drug degradation, gastric emptying, intestinal transit, first-pass metabolism, and intestinal transport. For future model development, more heterogeneous features of the gastrointestinal tract (villous blood flow, metabolizing enzymes, and transporters), food effects, and drug-drug interactions should be fully characterized and taken into consideration. Moreover, predicting population inter-and intravariability in oral drug absorption can be useful and important for the evaluation of clinical safety and efficacy of drugs. Establishing databases and libraries that contain accurate pharmaceutical and pharmacokinetic information for commercialized and uncommercialized drugs may also be helpful for model development and validation.KEY WORDS: advanced compartmental absorption and transit (ACAT) model; advanced dissolution, absorption, and metabolism (ADAM) model; compartmental model; dispersion model; oral drug absorption.

Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

“…Substrates of MCT1 demonstrate nonlinear absorption and bioavailability consistent with facilitated uptake (Arena and Fung, 1980;Cundy et al, 2004). Although MCT1 expression on the basolateral membrane of Caco-2 cells has not been reported, there are literature reports indicating that MCT1 is expressed on the basolateral membrane of intestinal cells, where it appears to function as an efflux transporter (Huang et al, 2009). Efflux of MCT1 substrates at the basolateral membrane of the intestine would contribute to the observed directional flux from the apical to basolateral membranes, as observed in the present study, and to the overall intestinal absorption of the substrate.…”

In silicoADME/T modelling for rational drug design

“…The ACAT approach is widely used and implemented in some commercially available software. More physiologically based models to predict oral drug absorption have been summarized by Huang et al (2009). The well-stirred model is a steady-state model for hepatic drug clearance that assumes that the liver is a well-stirred compartment and that the drug is distributed instantly and homogenously throughout the liver and plasma in blood (Wilkinson & Shand, 1975).…”

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

“…However, for compounds with a significant pH-dependent solubility or a high supersaturation propensity, measured equilibrium solubility at neutral pH may not adequately model dissolved drug concentration throughout the entire absorption window. In these cases, the use of biorelevant dissolution tools along with more sophisticated absorption modeling tools such as MiMBa®, GastroPlus®, STELLA®, or Simcyp® might be better suited [32][33][34][35][36]. The solid form from either undissolved or precipitated material should also be assessed as a change in polymorphic form can affect solubility and dissolution [37].…”