title: Cellular Uptake of Levocetirizine by Organic Anion Transporter 4.
abstract: The pharmacokinetics of cetirizine, a nonsedating antihistamine, is profoundly affected by transporter-mediated membrane transport in the kidney. In this study, we aimed to investigate the transport mechanism of levocetirizine, the pharmacologically active enantiomer of cetirizine, via human organic anion transporter 4 (OAT4) expressed in the apical membrane of renal proximal tubules and the basal plasma membrane of placental syncytiotrophoblasts. In cells expressing human OAT4 under the control of tetracycline, levocetirizine uptake was increased by tetracycline treatment. On the other hand, OAT4 expression did not facilitate efflux of preloaded levocetirizine from the cells, either in the presence or absence of extracellular Cl-. The OAT4-mediated levocetirizine uptake was concentration-dependent with a Kmof 38 μM. The uptake rate of levocetirizine via OAT4 was approximately twice that of racemic cetirizine, indicating stereoselective uptake of levocetirizine. On the other hand, OAT4-mediated [3H]dehydroepiandrosterone sulfate uptake was inhibited by dextrocetirizine and levocetirizine. Overall, our findings indicate that OAT4 mediates levocetirizine uptake but is unlikely to mediate the efflux.
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan.
authors.forename: Saya
authors.initials: S
authors.lastname: Mukaida
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan; Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California 94143-0912.
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
authors.affiliation: Faculty of Pharmacy, Keio University, Minato-ku 105-8512, Tokyo, Japan. Electronic address: tomi-ms@pha.keio.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
mesh_terms: D001692:Biological Transport; D002460:Cell Line; D017332:Cetirizine / Q000378:metabolism*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D029362:Organic Anion Transporters, Sodium-Independent; C498886:SLC22A9 protein, human; C472067:levocetirizine; D017332:Cetirizine
keywords: drug transport; membrane transport; organic anion transporters (OAT); pharmacokinetics; placenta; renal transport