title: In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.
abstract: The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.
authors.affiliation: Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya Minamigawara-cho, Yamashina-ku, Kyoto, 607-8042, Japan. matsuda_yoshiki@kaken.co.jp
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Konno
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Mika
authors.initials: M
authors.lastname: Nagai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Taguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satsukawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000042:Absorption; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D002404:Catheterization; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D008297:Male; D011169:Portal Vein; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012460:Sulfasalazine / Q000493:pharmacokinetics; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019772:Topotecan / Q000493:pharmacokinetics
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D003986:Dibenzocycloheptenes; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D011804:Quinolines; D012460:Sulfasalazine; D016593:Terfenadine; D019772:Topotecan; C095179:zosuquidar trihydrochloride; C093230:fexofenadine; D000241:Adenosine