title: Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists.
abstract: RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E max = 55%) showed a blood concentration higher than its E max after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [(11)C]1a, [(11)C]2a and fluorinated derivatives [(18)F]1b, [(18)F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.
authors: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors: Toshiki
authors: T
authors: Kobayashi
authors: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors: Yuki
authors: Y
authors: Furusawa
authors: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan ; Research Fellowship Division, Japan Society for the Promotion of Science , Sumitomo-Ichibancho FS Bldg., 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan.
authors: Shoya
authors: S
authors: Yamada
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Masaru
authors: M
authors: Akehi
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Fumiaki
authors: F
authors: Takenaka
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Takanori
authors: T
authors: Sasaki
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Akiya
authors: A
authors: Akahoshi
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Takahisa
authors: T
authors: Hanada
authors: Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors: Eiji
authors: E
authors: Matsuura
authors: SHI Accelerator Service Ltd. 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors: Hiroyuki
authors: H
authors: Hirano
authors: Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima , 562 Nanatsuka-Cho, Shobara, Hiroshima 727-0023, Japan.
authors: Akihiro
authors: A
authors: Tai
authors: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors: Hiroki
authors: H
authors: Kakuta
keywords: Nuclear receptors; PET imaging; RXR; pharmacokinetics