title: Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue.
abstract: A clear understanding of oral drug absorption is an important aspect of the drug development process. The permeability of drug compounds across intact sections of small intestine from numerous species, including man, has often been investigated using modified Ussing chambers. The maintenance of viable, intact tissue is critical to the success of this technique. This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross-species Ussing chamber studies. Electrical parameters (potential difference, mV; short-circuit current, µA.cm(-2) ; resistance, Ω.cm(2) ) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10(-6) ) for a training-set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco-2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeability values generated in rat and human jejunum correlate well (R(2) = 0.86), however the relationship between permeability in human tissue and Caco-2 cells was comparatively weak (R(2) = 0.58). Relating permeability to known human fraction absorbed (hFabs) values results in a remarkably similar relationship to both rat and human jejunum Papp values. It can be concluded that human jejunum sourced from pancreatoduodenectomy is a suitable source of tissue for Ussing chamber permeability investigations. The relationship between permeability and hFabs is comparable to results reported using alternative test compounds.
authors.affiliation: Drug Metabolism and Pharmacokinetics, AstraZeneca Research and Development, Alderley Park, Macclesfield, UK. iain.haslam@astrazeneca.com
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.forename: Derek A
authors.initials: DA
authors.lastname: O'Reilly
authors.forename: David J
authors.initials: DJ
authors.lastname: Sherlock
authors.forename: Ambareen
authors.initials: A
authors.lastname: Kauser
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001262:Atenolol / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D015194:Diffusion Chambers, Culture; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000502:physiology* / Q000601:surgery; D007583:Jejunum / Q000502:physiology* / Q000601:surgery; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D016577:Pancreaticoduodenectomy; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D057705:Transendothelial and Transepithelial Migration
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D004364:Pharmaceutical Preparations; D001262:Atenolol