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Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.
Mol Pharm 2009 Jan-Feb; 6(1):19-28MP

Abstract

The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels in this region.

Authors+Show Affiliations

College of Pharmacy, The University of Michigan, Ann Arbor, Michigan 48109-1065, USA.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19248230

Citation

Dahan, Arik, and Gordon L. Amidon. "Segmental Dependent Transport of Low Permeability Compounds Along the Small Intestine Due to P-glycoprotein: the Role of Efflux Transport in the Oral Absorption of BCS Class III Drugs." Molecular Pharmaceutics, vol. 6, no. 1, 2009, pp. 19-28.
Dahan A, Amidon GL. Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs. Mol Pharm. 2009;6(1):19-28.
Dahan, A., & Amidon, G. L. (2009). Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs. Molecular Pharmaceutics, 6(1), pp. 19-28. doi:10.1021/mp800088f.
Dahan A, Amidon GL. Segmental Dependent Transport of Low Permeability Compounds Along the Small Intestine Due to P-glycoprotein: the Role of Efflux Transport in the Oral Absorption of BCS Class III Drugs. Mol Pharm. 2009;6(1):19-28. PubMed PMID: 19248230.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs. AU - Dahan,Arik, AU - Amidon,Gordon L, PY - 2009/2/28/entrez PY - 2009/2/28/pubmed PY - 2009/3/24/medline SP - 19 EP - 28 JF - Molecular pharmaceutics JO - Mol. Pharm. VL - 6 IS - 1 N2 - The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels in this region. SN - 1543-8384 UR - https://www.unboundmedicine.com/medline/citation/19248230/Segmental_dependent_transport_of_low_permeability_compounds_along_the_small_intestine_due_to_P_glycoprotein:_the_role_of_efflux_transport_in_the_oral_absorption_of_BCS_class_III_drugs_ L2 - https://dx.doi.org/10.1021/mp800088f DB - PRIME DP - Unbound Medicine ER -