title: 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 the 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 Peffin rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peffin 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 the overall Peff. The jejunal and/or ileal Peffwas predicted for 12 (4) acidic, 13 (12) basic, 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logPo:w, and compared with experimental Peffobtained using SPIP. A key input is the intrinsic transcellular permeability (Ptrans,0) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The Peffpredictions were reasonably good when experimentally derived Ptrans,0was used; from 42 Peff,ratvalues, 24 (57%) were within 3-fold, and of 19 Peff,mousevalues, 12 (63%) were within 3-fold, of observed Peff. Considering the lack of alternative models to predict Peffin preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Blades Enterprise Centre, Simcyp Ltd (A Certara Company), John Street, Sheffield, S2 4SU, UK.
authors.forename: D
authors.identifier: http://orcid.org/0000-0003-0709-9528
authors.initials: D
authors.lastname: Pade
authors.affiliation: Blades Enterprise Centre, Simcyp Ltd (A Certara Company), John Street, Sheffield, S2 4SU, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jamei
authors.affiliation: Blades Enterprise Centre, Simcyp Ltd (A Certara Company), John Street, Sheffield, S2 4SU, UK.|Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, University of Manchester Medical School, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: A
authors.identifier: http://orcid.org/0000-0003-3917-844X
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Blades Enterprise Centre, Simcyp Ltd (A Certara Company), John Street, Sheffield, S2 4SU, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Turner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003106:Colon / Q000033:anatomy & histology / Q000378:metabolism*; D004058:Diffusion; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000378:metabolism*; D007421:Intestine, Small / Q000033:anatomy & histology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D004364:Pharmaceutical Preparations
keywords: MechPeff; bile salts; gut morphology; mechanistic prediction; rodent intestinal permeability