Regional Intestinal Permeability of Three Model Drugs in Human
2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, 3013-3021 p.Article in journal (Refereed) Published
Currently there are only a limited number of determinations of human P-eff 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 P-eff of each model drug was then calculated using a validated deconvolution method. The median P-eff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 X 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 X 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 X 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 P-eff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.
Place, publisher, year, edition, pages
2016. Vol. 13, no 9, 3013-3021 p.
intestinal permeability, regional intestinal drug absorption, effective permeability, pharmacokinetics
Pharmaceutical Sciences Gastroenterology and Hepatology
IdentifiersURN: urn:nbn:se:uu:diva-307864DOI: 10.1021/acs.molpharmaceut.6b00514ISI: 000382713700016PubMedID: 27504798OAI: oai:DiVA.org:uu-307864DiVA: diva2:1048903
FunderEU, FP7, Seventh Framework Programme, FP7/2007-013