Skip to Content
MilliporeSigma
  • Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption.

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption.

The AAPS journal (2015-05-20)
Andrés Olivares-Morales, Hans Lennernäs, Leon Aarons, Amin Rostami-Hodjegan
ABSTRACT

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 P(eff) values or "intrinsic" P(eff)(P(eff,int)) were subsequently employed for the prediction of the ileal absorption clearance (CL(abs,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 P(eff,int) can successfully be employed for the prediction of the ileal CL(abs) and the f(abs). P(eff,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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Salicylic acid, ≥99%, FG
Sigma-Aldrich
Salicylic acid, ReagentPlus®, ≥99%
Sigma-Aldrich
Salicylic acid, puriss. p.a., ≥99.0% (T)
Sigma-Aldrich
Salicylic acid, meets analytical specification of Ph. Eur., BP, USP, 99.5-100.5% (calc. to the dried substance)
Sigma-Aldrich
Salicylic acid, suitable for plant cell culture
Sigma-Aldrich
Salicylic acid, BioXtra, ≥99.0%
Supelco
Salicylic acid, 1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Salicylic acid, ACS reagent, ≥99.0%
Sigma-Aldrich
Cimetidine
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Sigma-Aldrich
Hydrochlorothiazide, meets USP testing specifications
Sigma-Aldrich
Hydrochlorothiazide, crystalline
Sigma-Aldrich
Acetaminophen, analytical standard
Supelco
Acetaminophen solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®