title: Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier.
abstract: Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [(3) H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with a Km of 20 μM, and was increased in the absence of chloride. [(3) H]Olmesartan efflux via OAT4 was also observed and was trans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS.
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Ayasa
authors.initials: A
authors.lastname: Fujibayashi
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8512, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D013448:Sulfobromophthalein / Q000494:pharmacology; D013777:Tetrazoles / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002712:Chlorides; D007093:Imidazoles; D027361:Organic Anion Transporters; D013777:Tetrazoles; D013448:Sulfobromophthalein; D004970:Estrone; D019314:Dehydroepiandrosterone Sulfate; C437965:olmesartan; C017296:estrone sulfate
keywords: membrane transport; membrane transporter; organic anion transporters (OAT); pharmacokinetics; placenta; pregnancy