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摘要
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 (P-eff) 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 P-eff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict P-eff 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 the overall P-eff. The jejunal and/or ileal P-eff was 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 logP(o:w) and compared with experimental P-eff obtained using SPIP. A key input is the intrinsic transcellular permeability (P-trans,P-0) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The P-eff predictions were reasonably good when experimentally derived P-trans,P-0 was used; from 42 P-eff,(rat) values, 24 (57%) were within 3-fold, and of 19 P-eff,P-mouse values, 12 (63%) were within 3-fold, of observed P-eff. Considering the lack of alternative models to predict P-eff in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes.
- 出版日期2017-3
