title: Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms.
abstract: 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.
authors: Department of Pharmacy, Uppsala University , Uppsala SE-751 23, Sweden.
authors: David
authors: D
authors: Dahlgren
authors: Department of Pharmacy, Uppsala University , Uppsala SE-751 23, Sweden.
authors: Carl
authors: C
authors: Roos
authors: AstraZeneca R&D , Gothenburg SE-431 50, Sweden.
authors: Pernilla
authors: P
authors: Johansson
authors: AstraZeneca R&D , Gothenburg SE-431 50, Sweden.
authors: Anders
authors: A
authors: Lundqvist
authors: AstraZeneca R&D , Gothenburg SE-431 50, Sweden.
authors: Christer
authors: C
authors: Tannergren
authors: AstraZeneca R&D , Gothenburg SE-431 50, Sweden.
authors: Bertil
authors: B
authors: Abrahamsson
authors: Department of Pharmacy, Uppsala University , Uppsala SE-751 23, Sweden.
authors: Erik
authors: E
authors: Sjögren
authors: Department of Pharmacy, Uppsala University , Uppsala SE-751 23, Sweden.
authors: Hans
authors: H
authors: Lennernäs
mesh_terms: D000818:Animals; D001262:Atenolol / Q000493:pharmacokinetics; D004285:Dogs; D015773:Enalaprilat / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D007420:Intestine, Large / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D007660:Ketoprofen / Q000493:pharmacokinetics; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics; D010539:Permeability
chemical_list: D001262:Atenolol; D007660:Ketoprofen; D008790:Metoprolol; D015773:Enalaprilat
keywords: bioavailability; dog intestinal permeability; effective permeability; intestinal perfusion; pharmaceutical development; pharmacokinetics; regional intestinal drug absorption