title: A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices.
abstract: A reliable prediction of the oral bioavailability in humans is crucial and of high interest for pharmaceutical and food industry. The predictive value of currently used in silico methods, in vitro cell lines, ex vivo intestinal tissue and/or in vivo animal studies for human intestinal absorption, however, is often insufficient, especially when food-drug interactions are evaluated. Ideally, for this purpose healthy human intestinal tissue is used, but due to its limited availability there is a need for alternatives. The aim of this study was to evaluate the applicability of healthy porcine intestinal tissue mounted in a newly developed InTESTine™ system to predict human intestinal absorption of compounds with different chemical characteristics, and within biorelevant matrices. To that end, first, a representative set of compounds was chosen of which the apparent permeability (Papp) data in both Caco-2 cells and human intestinal tissue mounted in the Ussing chamber system, and absolute human oral bioavailability were reported. Thereafter, Papp values of the subset were determined in both porcine jejunal tissue and our own Caco-2 cells. In addition, the feasibility of this new approach to study regional differences (duodenum, jejunum, and ileum) in permeability of compounds and to study the effects of luminal factors on permeability was also investigated. For the latter, a comparison was made between the compatibility of porcine intestinal tissue, Caco-2 cells, and Caco-2 cells co-cultured with the mucin producing HT29-MTX cells with biorelevant samples as collected from an in vitro dynamic gastrointestinal model (TIM). The results demonstrated that for the paracellularly transported compounds atenolol, cimetidine, mannitol and ranitidine porcine Papp values are within 3-fold difference of human Papp values, whereas the Caco-2 Papp values are beyond 3-fold difference. Overall, the porcine intestinal tissue Papp values are more comparable to human Papp values (9 out of 12 are within 3-fold difference), compared to Caco-2 Papp values (4 out of 12 are within 3-fold difference). In addition, for the selected hydrophilic compounds a significant increase in the permeability was observed from duodenum to ileum. Finally, this study indicated that porcine jejunal tissue segments can be used with undiluted luminal samples to predict human intestinal permeability and the effect of biorelevant matrices on this. In conclusion, viable porcine intestinal tissue mounted in the InTESTine™ system can be applied as a reliable tool for the assessment of intestinal permeability in the absence and presence of biorelevant samples. This would enable an accessible opportunity for a reliable prediction of human intestinal absorption, and the effect of luminal compounds such as digested foods, early in drug development.
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Westerhout
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Evita
authors.initials: E
authors.lastname: van de Steeg
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Grossouw
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Evelijn E
authors.initials: EE
authors.lastname: Zeijdner
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Cyrille A M
authors.initials: CA
authors.lastname: Krul
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Verwei
authors.affiliation: The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands. Electronic address: heleen.wortelboer@tno.nl.
authors.forename: Heleen M
authors.initials: HM
authors.lastname: Wortelboer
mesh_terms: D000818:Animals; D001262:Atenolol / Q000737:chemistry / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002927:Cimetidine / Q000737:chemistry / Q000493:pharmacokinetics; D019073:HT29 Cells; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008353:Mannitol / Q000737:chemistry / Q000493:pharmacokinetics; D010539:Permeability; D011899:Ranitidine / Q000737:chemistry / Q000493:pharmacokinetics; D013552:Swine; D014407:Tumor Cells, Cultured
chemical_list: D008353:Mannitol; D001262:Atenolol; D002927:Cimetidine; D011899:Ranitidine
keywords: Antipyrine; Atenolol; Caco-2; Caffeine; Cimetidine; Digoxin; Food-effect; Human intestine; InTESTine™; Intestinal absorption; Mannitol; Porcine intestine; Propranolol; Ranitidine; Testosterone; Verapamil