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Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.
Eur J Pharm Sci 2012; 46(5):367-73EJ

Abstract

The purpose of this study was to validate human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for predicting the oral drug absorption in humans with the main focus on moderately and poorly permeable compounds. The obtained apparent permeability coefficient (P(app)) of eleven test compounds was compared to their fraction absorbed (Fa) in humans taken from the literature. Beside the conventional P(app) a new parameter, the apparent permeability coefficient total (P(app,total)), involving both the apical-to-basolateral permeability and the time-dependent compound accumulation in the tissue was established. The permeability of lucifer yellow (LY), a fluorescent marker of the paracellular pathway and the test compounds showed no obvious differences between small intestine and colon. Furthermore, small intestinal and colonic tissue from a single donor showed similar permeability of both LY and a transcellularly transported compound metoprolol. All test compounds including low molecular weight hydrophilic compounds such as metformin, atenolol, sulpiride and famotidine showed adequate permeability reflecting human Fa values (R(2)=0.87). The P(app) values of digoxin, a P-glycoprotein (P-gp) substrate, were not significantly affected by the addition of verapamil, a P-gp inhibitor. In contrast, the P(app,total) values of digoxin increased approximately threefold in the presence of verapamil. In conclusion, both small intestinal and colonic tissue mounted in the Ussing chamber provide a good opportunity to predict the oral drug absorption rate in humans even for moderately and poorly absorbed compounds. The novel calculation of P(app,total) allows the study of the carrier-mediated drug-drug interactions in human intestine.

Authors+Show Affiliations

Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Bunsenstrasse 7, 82152 Martinsried, Germany. veronika.rozehnal@daiichi-sankyo.euNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Validation Studies

Language

eng

PubMed ID

22418036

Citation

Rozehnal, Veronika, et al. "Human Small Intestinal and Colonic Tissue Mounted in the Ussing Chamber as a Tool for Characterizing the Intestinal Absorption of Drugs." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 46, no. 5, 2012, pp. 367-73.
Rozehnal V, Nakai D, Hoepner U, et al. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs. Eur J Pharm Sci. 2012;46(5):367-73.
Rozehnal, V., Nakai, D., Hoepner, U., Fischer, T., Kamiyama, E., Takahashi, M., ... Mueller, J. (2012). Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 46(5), pp. 367-73. doi:10.1016/j.ejps.2012.02.025.
Rozehnal V, et al. Human Small Intestinal and Colonic Tissue Mounted in the Ussing Chamber as a Tool for Characterizing the Intestinal Absorption of Drugs. Eur J Pharm Sci. 2012 Aug 15;46(5):367-73. PubMed PMID: 22418036.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs. AU - Rozehnal,Veronika, AU - Nakai,Daisuke, AU - Hoepner,Ursula, AU - Fischer,Thomas, AU - Kamiyama,Emi, AU - Takahashi,Masayuki, AU - Yasuda,Satoru, AU - Mueller,Juergen, Y1 - 2012/03/07/ PY - 2011/12/07/received PY - 2012/02/27/revised PY - 2012/02/27/accepted PY - 2012/3/16/entrez PY - 2012/3/16/pubmed PY - 2012/9/12/medline SP - 367 EP - 73 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 46 IS - 5 N2 - The purpose of this study was to validate human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for predicting the oral drug absorption in humans with the main focus on moderately and poorly permeable compounds. The obtained apparent permeability coefficient (P(app)) of eleven test compounds was compared to their fraction absorbed (Fa) in humans taken from the literature. Beside the conventional P(app) a new parameter, the apparent permeability coefficient total (P(app,total)), involving both the apical-to-basolateral permeability and the time-dependent compound accumulation in the tissue was established. The permeability of lucifer yellow (LY), a fluorescent marker of the paracellular pathway and the test compounds showed no obvious differences between small intestine and colon. Furthermore, small intestinal and colonic tissue from a single donor showed similar permeability of both LY and a transcellularly transported compound metoprolol. All test compounds including low molecular weight hydrophilic compounds such as metformin, atenolol, sulpiride and famotidine showed adequate permeability reflecting human Fa values (R(2)=0.87). The P(app) values of digoxin, a P-glycoprotein (P-gp) substrate, were not significantly affected by the addition of verapamil, a P-gp inhibitor. In contrast, the P(app,total) values of digoxin increased approximately threefold in the presence of verapamil. In conclusion, both small intestinal and colonic tissue mounted in the Ussing chamber provide a good opportunity to predict the oral drug absorption rate in humans even for moderately and poorly absorbed compounds. The novel calculation of P(app,total) allows the study of the carrier-mediated drug-drug interactions in human intestine. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/22418036/Human_small_intestinal_and_colonic_tissue_mounted_in_the_Ussing_chamber_as_a_tool_for_characterizing_the_intestinal_absorption_of_drugs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(12)00103-0 DB - PRIME DP - Unbound Medicine ER -