Burckhardt. Transport of cimetidine by flounder and human renal organic anion transporter 1. Am J Physiol Renal Physiol 284: F503-F509, 2003. First published November 12, 2002 10.1152/ajprenal.00290.2002The H 2-receptor antagonist cimetidine is efficiently excreted by the kidneys. In vivo studies indicated an interaction of cimetidine not only with transporters for basolateral uptake of organic cations but also with those involved in excretion of organic anions. We therefore tested cimetidine as a possible substrate of the organic anion transporters cloned from winter flounder (fROAT) and from human kidney (hOAT1). Uptake of [ 3 H]cimetidine into fROAT-expressing Xenopus laevis oocytes exceeded uptake into control oocytes. At Ϫ60-mV clamp potential, 1 mM cimetidine induced an inward current, which was smaller than that elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH-induced inward currents, indicating interaction with the same transporter. At pH 6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was readily detectable, suggesting preferential translocation of uncharged cimetidine by fROAT. Oocytes expressing hOAT1 also showed [ 3 H]cimetidine uptake. These data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic anion transporters contribute to cimetidine excretion in proximal tubules.winter flounder renal organic anion transporter; organic anion transport; organic cation transport; kidney AS A SPECIFIC ANTAGONIST OF histamine H 2 receptors, cimetidine acts on gastric parietal cells to inhibit HCl secretion stimulated by histamine, pentagastrin, and acetylcholine. Between 50 and 80% of the dose administered intravenously was recovered in urine as unchanged cimetidine, and elimination half-life was ϳ2 h in healthy volunteers with normal kidney and hepatic function (24). The mean steady-state plasma concentration on a standard 1,000-mg daily dose was 1 g/ml (range 0.64-1.64 g/ml). A renal clearance of 600 ml/ min (24), exceeding the glomerular filtration rate by approximately fivefold, indicated an efficient tubular secretion of cimetidine. Therefore, cimetidine must interact with renal transporters, most probably with those located in the proximal tubules.Because at physiological pH part of the cimetidine is positively charged, the organic cation transport systems of the proximal tubule cell are expected to be involved in cimetidine secretion. The two-step model of transcellular organic cation secretion consists of electrogenic uptake at the basolateral side, moving organic cations down their electrochemical gradient from blood into proximal tubular cells, and organic cation/proton exchange mediating uphill exit into the lumen. The cloned organic cation transporters, OCT1, OCT2, and OCT3, are electrogenic and likely contribute to organic cation uptake across the basolateral membrane (for reviews, see Refs. 6 and 18). In accordance with their function, rat OCT1 and OCT2 were localized to the basolateral membrane of proximal tubule ce...