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.
Highlights
Drug excretion into saliva has important clinical implications, but the mechanisms underlying salivary gland drug transport remain unclear
Drugs are known to be excreted into saliva; other than passive diffusion, the molecular mechanisms by which salivary gland epithelial cells secret xenobiotics are virtually unknown [4, 5]
As Oct3 expression was less studied in mice, we first quantified mRNA expression of Oct3 and other known metformin transporters, including Oct1, Oct2, Mate1, and Pmat, in various mouse tissues relevant to metformin disposition and response (Fig. 2)
Summary
Drug excretion into saliva has important clinical implications, but the mechanisms underlying salivary gland drug transport remain unclear. Results: OCT3 is highly expressed in secretory epithelial cells and mediates active metformin transport in salivary glands. A widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct in vitro. Oct3؊/؊ mice 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. Drugs are known to be excreted into saliva; other than passive diffusion, the molecular mechanisms by which salivary gland epithelial cells secret xenobiotics are virtually unknown [4, 5]. OCT3 and PMAT, two newer polyspecific organic cation transporters with a broad tissue distribution, transport metformin in vitro [12, 14] Their roles in metformin disposition and action in vivo are less clear. Transport was evaluated in mice with targeted deletion of the Oct3/Slc22a3 gene
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