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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)

Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (D.L.B., D.R.T.); and Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.B.P.)

Human organic cation transporters (hOCTs) are expressed in organs of drug absorption and elimination and play an important role in the uptake and elimination of xenobiotics. The purpose of this study was to evaluate the substrate and inhibitory activity of the H₂-receptor antagonists ranitidine and famotidine toward hOCTs and to determine the hOCT isoforms involved in the absorption and elimination of these compounds in humans. Inhibition and substrate specificity of hOCT1, hOCT2, and hOCT3 for ranitidine and famotidine were elucidated in cRNA-injected Xenopus laevis oocytes. Ranitidine and famotidine exhibited similarly potent inhibition of [³H]1-methyl-4-phenyl pyridinium uptake into hOCT1-expressing (IC₅₀ = 33 and 28 µM, respectively) and hOCT2-expressing oocytes (IC₅₀ = 76 and 114 µM, respectively). Famotidine exhibited potent inhibition of hOCT3; in contrast, ranitidine was a moderately weak inhibitor (IC₅₀ = 6.7 and 290 µM, respectively). [³H]Ranitidine uptake was stimulated by hOCT1 (K_m = 70 ± 9 µM) and to a much smaller extent by hOCT2. No stimulation of [³H]ranitidine uptake was observed in hOCT3-expressing oocytes. trans-Stimulation and electrophysiology studies suggested that famotidine also is an hOCT1 substrate and exhibits poor or no substrate activity toward hOCT2 and hOCT3. Thus, hOCT1, which is expressed in the intestine and liver, is likely to play a major role in the intestinal absorption and hepatic disposition of ranitidine and famotidine in humans, whereas hOCT2, the major isoform present in the kidney, may play only a minor role in their renal elimination. Famotidine seems to be one of the most potent inhibitors of hOCT3 yet identified.

Address correspondence to: Dr. Dhiren R. Thakker, Division of Drug Delivery and Disposition, School of Pharmacy, Kerr Hall, CB 7360, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: dhiren_thakker{at}unc.edu

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