Papers - ITAGAKI Shiro

Biliary excretion of irinotecan and its metabolites.

T Itoh, Takemoto, I, S Itagaki, K Sasaki, T Hirano, K Iseki

JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES ( CANADIAN SOC PHARMACEUTICAL SCIENCES )  7 ( 1 ) 13 - 18  2004.01  [Refereed]

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PURPOSE: The aim of this study was to investigate the excretion of irinotecan hydrochloride (CPT-11) and its metabolites into the gastrointestinal lumen via the biliary route after intravenous administration of lactone and carboxylate forms of CPT-11. METHODS: Biliary excretions of CPT-11 and its metabolites, SN-38 and SN-38-glucuronide, were investigated by an in vivo administration study using rats. The biliary excretion profiles for both the lactone and carboxylate forms of CPT-11 and its metabolites were determined. RESULTS: After the i.v. injection of the lactone form of CPT-11, the cumulative biliary excretion of SN-38-glucuronide was much greater than that of CPT-11 and SN-38, and biliary excretion of SN-38 was less than that of CPT-11. Further, CPT-11 and SN-38 were mainly excreted into bile as carboxylate forms. After the administration of the CPT-11 carboxylate form, biliary excretion of SN-38-glucuronide was significantly smaller than that after the administration of CPT-11 lactone form. On the other hand, biliary excretion of CPT-11 and SN-38 was greater after dosing with the CPT-11 carboxylate form than that after the CPT-11 lactone form. CONCLUSIONS: The results suggest that the rate of conversion of lactone to carboxylate forms of CPT-11 and its metabolites plays a major role in the biliary excretion of these compounds.

PubMed

Comparison of the Disposition Behavior of Organic anions in an Animal Model for Wilson's Disease (Long-Evans Cinnamon rats) with that in Normal Long-Evans Agouti rats

Shirou Itagaki, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki, Takeshi Hirano, Ken Iseki

Drug Metabolism and Pharmacokinetics ( Japanese Society for the Study of Xenobiotics )  19 ( 2 ) 150 - 154  2004  [Refereed]

DOI PubMed CiNii

Major role of organic anion transporters in the uptake of phenolsulfonphthalein in the kidney

S Itagaki, M Sugawara, M Kobayashi, S Nishimura, M Fujimoto, K Miyazaki, K Iseki

EUROPEAN JOURNAL OF PHARMACOLOGY ( ELSEVIER SCIENCE BV )  475 ( 1-3 ) 85 - 92  2003.08  [Refereed]

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Phenolsulfonphthalein is used for testing renal function. However, its excretion mechanism has not been elucidated. The purpose of this study was therefore to elucidate the transporter-mediated excretion system for phenolsulfonphthalein. p-Aminohippuric acid, a substrate of rat organic anion transporter1 (rOat1), and cimetidine, a substrate of rOat3, reduced the urinary excretion of phenolsulfonphthalein. The uptake of phenolsulfonphthalein by kidney slices was found to consist of two components. The IC50 values of rOat1 substrates were higher than those of rOat3 substrates. In the presence of cimetidine, the Eadie-Hofstee plot gave a single straight line. The profile of the phenolsulfonphthalein uptake component in the presence of cimetidine was similar to that of the low-affinity component in the absence of cimetidine. We conclude that rOat1 and rOat3 are involved in the renal uptake of phenolsulfonphthalein and that phenolsulfonphthalein is a high-affinity substrate for rOat3 but is a relatively low-affinity substrate for rOat1. (C) 2003 Elsevier B.V. All rights reserved.

DOI PubMed

Mechanism of Active Secretion of Phenolsulfonphthalein in the Liver via Mrp2 (abcc2), an Organic Anion Transporter

Shirou Itagaki, Ken Iseki, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki

Drug Metabolism and Pharmacokinetics ( 4 )  18 ( 4 ) 238 - 244  2003  [Refereed]

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Phenolsulfonphthalein (PSP) has been selected as a model drug that is eliminated from both the kidney and liver in rats. Although the renal PSP transport system has been studied, few details of the biliary excretion of PSP have been reported. We investigated the biliary excretion system for PSP in rats. It has been reported that the biliary excretion of many organic anions from hepatocytes into bile is mediated by a primary active transporter, referred to as multidrug resistance-associated protein 2 (Mrp2/abcc2). The biliary excretion of PSP in SD rats was significantly decreased in the presence of Mrp2 inhibitors. The biliary excretion of PSP in Eisai hyperbilirubinemic rats (EHBR), hereditarily Mrp2-defective rats, was significantly lower than that in SD rats. Moreover, an efflux experiment using Caco-2 cells was carried out to confirm Mrp2-mediated PSP transport. Mrp2 inhibitors significantly decreased PSP efflux from Caco-2 cells. These results suggest that Mrp2 contributes to the biliary excretion of PSP in SD rats. © 2003, The Japanese Society for the Study of Xenobiotics. All rights reserved.

DOI CiNii