Involvement of rat and human organic anion transporter 3 in the renal tubular secretion of topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride].
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 microM, 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 microM, 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.
Matsumoto
Shin-ichi
S
Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
Yoshida
Kenji
K
Ishiguro
Naoki
N
Maeda
Tomoji
T
Tamai
Ikumi
I
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D050533:Glomerular Basement Membrane; D005919:Glomerular Filtration Rate; D006801:Humans; D007684:Kidney Tubules; D009865:Oocytes; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019772:Topotecan / Q000493:pharmacokinetics*; D014161:Transduction, Genetic
D000970:Antineoplastic Agents; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D019772:Topotecan