Application of the MechPeff Model to Predict Passive Effective Intestinal Permeability in the Different Regions of the Rodent Small Intestine and Colon

Abstract A major component of Physiologically‐Based Pharmacokinetic (PBPK) models is prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff) is essential. Single pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the ‘MechPeff’ model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug‐specific physicochemical parameters. The ‘MechPeff’ model, built‐in to the Simcyp Rat and Mouse Simulators, predicts transcellular, paracellular and mucus layer permeabilities and combines these to give overall Peff. Jejunal and/or ileal Peff was predicted for 12 (4) acidic, 13 (12) basic and 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logPo:w and compared to experimental Peff obtained using SPIP. A key input is intrinsic transcellular permeability (Ptrans,0) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. Peff predictions were reasonably good when experimentally‐derived Ptrans,0 was used; from 42 Peff,rat values 24 (57%) were within 3‐fold, and of 19 Peff,mouse values, 12 (63%) were within 3‐fold, o...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research