title: Human organic cation transporter 2 (hOCT2): Inhibitor studies using S2-hOCT2 cells.
abstract: Highly expressed in kidney and located on the basolateral membrane, human organic cation transporter 2 (hOCT2) can transport various compounds (i.e. drugs and toxins) into the proximal tubular cell. Using cultured proximal tubule cells stably expressing hOCT2 (i.e. S2-hOCT2 cells), we sought to probe different compound classes (e.g. analgesics, anti-depressants, anti-psychotics, disinfectant, herbicides, insecticides, local anesthetic, muscarinic acetylcholine receptor antagonist, sedatives, steroid hormone, stimulants and toxins) for their ability to inhibit (14)C-TEA uptake, a prototypical OCT2 substrate. Aconitine, amitriptyline, atropine, chlorpyrifos, diazepam, fenitrothion, haloperidol, lidocaine, malathion, mianserin, nicotine and triazolam significantly inhibited (14)C-TEA uptake; IC50 values were 59.2, 2.4, 2.0, 20.7, 32.3, 13.2, 32.5, 104.6, 71.1, 17.7, 52.8 and 65.5μM, respectively. In addition, aconitine, amitriptyline, atropine, chlorpyrifos, fenitrothion, haloperidol, lidocaine, and nicotine displayed competitive inhibition with Ki values of 145.6, 2.5, 2.4, 24.8, 16.9, 51.6, 86.8 and 57.7μM, respectively. These in vitro data support the notion that compounds pertaining to a wide variety of different drug classes have the potential to decrease renal clearance of drugs transported via hOCT2. Consequently, these data warrant additional studies to probe hOCT2 and its role to influence drug pharmacokinetics.
authors.affiliation: Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan. chiba@marianna-u.ac.jp
authors.forename: Shoetsu
authors.initials: S
authors.lastname: Chiba
authors.forename: Toru
authors.initials: T
authors.lastname: Ikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshita
authors.forename: Sanae
authors.initials: S
authors.lastname: Kanno
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nagai
authors.forename: Meri
authors.initials: M
authors.lastname: Takada
authors.forename: Toshiji
authors.initials: T
authors.lastname: Mukai
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
mesh_terms: D018929:Cell Culture Techniques; D002460:Cell Line; D002853:Chromatography, Liquid; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D019789:Tetraethylammonium / Q000032:analysis / Q000493:pharmacokinetics; D014162:Transfection
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations; C491013:SLC22A2 protein, human; D019789:Tetraethylammonium
keywords: Human organic cation transporter 2 (hOCT2); Inhibitors; Renal excretion