Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption
2015 (English)In: AAPS Journal, ISSN 1550-7416, Vol. 17, no 5, 1177-1192 p.Article in journal (Refereed) Published
Regional intestinal effective permeability (P-eff) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P-eff values. These new intestinal Peff values or "intrinsic" P-eff(P-eff,P-int) were subsequently employed for the prediction of the ileal absorption clearance (CLabs,ileum) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that Peff, int can successfully be employed for the prediction of the ileal CLabs and the f(abs). P-eff,P-int also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P-eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.
Place, publisher, year, edition, pages
2015. Vol. 17, no 5, 1177-1192 p.
intestinal permeability, oral drug absorption, physiologically based pharmacokinetic modelling
Pharmaceutical Sciences Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-262950DOI: 10.1208/s12248-015-9758-0ISI: 000360364500013PubMedID: 25986421OAI: oai:DiVA.org:uu-262950DiVA: diva2:858403