title: Regional Intestinal Permeability of Three Model Drugs in Human.
abstract: Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.
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, Sweden.
authors: Anders
authors: A
authors: Lundqvist
authors: AstraZeneca R&D , Gothenburg, Sweden.
authors: Bertil
authors: B
authors: Abrahamsson
authors: AstraZeneca R&D , Gothenburg, Sweden.
authors: Christer
authors: C
authors: Tannergren
authors: Department of Medical Sciences, Uppsala University , Uppsala SE-751 05, Sweden.
authors: Per M
authors: PM
authors: Hellström
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: D000293:Adolescent; D000328:Adult; D001262:Atenolol / Q000378:metabolism / Q000493:pharmacokinetics; D003106:Colon / Q000378:metabolism; D005260:Female; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D007660:Ketoprofen / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008790:Metoprolol / Q000378:metabolism / Q000493:pharmacokinetics; D008875:Middle Aged; D010539:Permeability; D055815:Young Adult
chemical_list: D001262:Atenolol; D007660:Ketoprofen; D008790:Metoprolol
keywords: effective permeability; intestinal permeability; pharmacokinetics; regional intestinal drug absorption