title: Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands.
abstract: Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family. OCT3 protein is localized at both basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both epithelial uptake and efflux of organic cations in the secretory cells of salivary glands. Metformin, a widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct3 in vitro. In vivo, metformin was actively transported with a high level of accumulation in the salivary glands of wild-type mice. In contrast, active uptake and accumulation of metformin in salivary glands were abolished in Oct3(-/-) mice. Oct3(-/-) mice also showed altered metformin pharmacokinetics and reduced drug exposure in the heart. These results demonstrate that OCT3 is responsible for metformin accumulation and secretion in salivary glands. Our study uncovered a novel carrier-mediated pathway for drug entry into saliva and sheds new light on the molecular mechanisms underlying drug-induced taste disorders.
authors.affiliation: Departments of Pharmaceutics, University of Washington, Seattle, Washington 98195.
authors.forename: Nora
authors.initials: N
authors.lastname: Lee
authors.affiliation: Departments of Pharmaceutics, University of Washington, Seattle, Washington 98195.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Duan
authors.affiliation: Departments of Pharmacy, University of Washington, Seattle, Washington 98195; Departments of Obstetrics and Gynecology, and University of Washington, Seattle, Washington 98195.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
authors.affiliation: Departments of Biostatistics, University of Washington, Seattle, Washington 98195.
authors.forename: C Jason
authors.initials: CJ
authors.lastname: Liang
authors.affiliation: Departments of Biostatistics, University of Washington, Seattle, Washington 98195.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.affiliation: Departments of Pharmaceutics, University of Washington, Seattle, Washington 98195. Electronic address: jowang@uw.edu.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008687:Metformin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D012469:Salivary Glands / Q000378:metabolism* / Q000473:pathology; D013651:Taste Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D007004:Hypoglycemic Agents; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D008687:Metformin
keywords: Diabetes; Drug Transport; Membrane Transport; Metformin; Organic Cation Transporter 3; Pharmacokinetics; Salivary Gland; Transporter
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