Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms

Mol Pharm. 2016 Sep 6;13(9):3022-33. doi: 10.1021/acs.molpharmaceut.6b00515. Epub 2016 Aug 18.


The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.

Keywords: bioavailability; dog intestinal permeability; effective permeability; intestinal perfusion; pharmaceutical development; pharmacokinetics; regional intestinal drug absorption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atenolol / pharmacokinetics
  • Dogs
  • Enalaprilat / pharmacokinetics
  • Humans
  • Intestinal Absorption
  • Intestine, Large / metabolism*
  • Intestine, Small / metabolism*
  • Jejunum / metabolism
  • Ketoprofen / pharmacokinetics
  • Male
  • Metoprolol / pharmacokinetics
  • Permeability


  • Atenolol
  • Ketoprofen
  • Metoprolol
  • Enalaprilat