QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.123323v1 322/3/1246    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsumoto, S.-i. Articles by Tamai, I. Search for Related Content PubMed PubMed Citation Articles by Matsumoto, S.-i. Articles by Tamai, I. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]

Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride] is primarily excreted into urine in humans, with approximately 49% of the dose recovered as total topotecan (topotecan lactone plus topotecan hydroxyl acid form). The renal elimination of topotecan involves tubular secretion in addition to glomerular filtration, but little is known about the molecular mechanism of the renal tubular secretion. In the present study, we investigated the transport characteristics of topotecan hydroxyl acid across the renal basolateral membrane using rat kidney slices and rat or human transporter-expressing Xenopus laevis oocytes. Pravastatin and probenecid significantly inhibited the uptake of topotecan hydroxyl acid by rat kidney slices with K_i values of 10.6 and 8.1 µM, respectively, and p-aminohippurate was weakly inhibitory at high concentrations, whereas excess tetraethylammonium had no effect. The uptake of topotecan hydroxyl acid by oocytes injected with complementary RNA of either rat or human organic anion transporter 3 (rOAT3 or hOAT3) was greater than that of water-injected oocytes. Kinetic analysis showed that the K_m values for rOAT3 and hOAT3 were 21.9 and 56.5 µM, respectively. Neither rOAT1 nor hOAT1 stimulated topotecan hydroxyl acid transport. These results suggest that the urinary excretion of topotecan hydroxyl acid is accounted for by transport via OAT3, as well as glomerular filtration, in both rats and humans; therefore, drug-drug interactions involving OAT3 may cause a change in clearance of topotecan.

Address correspondence to: Dr. Professor Ikumi Tamai, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan. E-mail: tamai{at}rs.noda.tus.ac.jp

This article has been cited by other articles:

				J. Shen, A. M. Carcaboso, K. E. Hubbard, M. Tagen, H. G. Wynn, J. C. Panetta, C. M. Waters, M. A. Elmeliegy, and C. F. Stewart Compartment-Specific Roles of ATP-Binding Cassette Transporters Define Differential Topotecan Distribution in Brain Parenchyma and Cerebrospinal Fluid Cancer Res., July 15, 2009; 69(14): 5885 - 5892. [Abstract] [Full Text] [PDF]

				M. Nakakariya, Y. Shima, Y. Shirasaka, K. Mitsuoka, T. Nakanishi, and I. Tamai Organic anion transporter OAT1 is involved in renal handling of citrulline Am J Physiol Renal Physiol, July 1, 2009; 297(1): F71 - F79. [Abstract] [Full Text] [PDF]

				J. R. Molina, S. H. Kaufmann, J. M. Reid, S. D. Rubin, M. Galvez-Peralta, R. Friedman, K. S. Flatten, K. M. Koch, T. M. Gilmer, R. J. Mullin, et al. Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data Clin. Cancer Res., December 1, 2008; 14(23): 7900 - 7908. [Abstract] [Full Text] [PDF]