|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Human organic anion transporter (hOAT) and human organic cation transporter (hOCT) play important roles in the tubular secretion of drugs. HOAT1, 2, 3, hOCT2 are localized to the basolateral side of the proximal tubule and mediate the uptake of drugs into the proximal tubule. HOAT4 is localized to the apical side of the proximal tubule and mediates the urinary secretion or the reabsorption of drugs. Using cell lines stably expressing these transporters, we have obtained the results as below. 1. Identification of transporters responsible for drug transport: HOATs and hOCTs responsible for renal drug transport were identified as follows; (1) Prostaglandin E2α F2: hOAT1, 2, 3, 4, hOCT1, 2, (2) Antivirals (Acyclovir and Ganciclovir): hOAT1, hOCT1, (3) Antiviral (Zidovudine): hOAT1, 2, 3, 4, (4) Antitumor dug (Methotrexate): hOAT1, 3, 4, (5) Tetracycline: hOAT1, 2, 3, 4, (6) Mycotoxin (Ochratoxin A): hOAT1, 3, 4, (7) Uremic toxin (Indoxyl sulfate): rat-OAT1, OAT3. In (3), it was predicted that the molecule responsible for the drug interaction between methotrexate and nonsteroidal antiinflammatory drugs is hOAT3. 2. Evaluation of organic anion transport inhibitors: We undertook to predict the target hOATs for betamipron and cilastatin, which are co-administered with carbapenpen antibiotics, and probenecid in vivo. It was predicted that betamipron inhibits hOAT1, 3, cilastatin dose hOAT1, and probenecid dose hOAT4 in vivo. 3. Elucidation of OAT in the induction of drug-induced nephrotoxicity: It was suggested that hOAT1, 3 are associated with the induction of odhratoxin A-induced nephrotoxicity, and rOAT1 and rOAT3 are associated with the induction of indoxyl sulfate-induced nephrotoxicity. The current results provide not only the molecular basis for renal drug transport, but also the information for the safer and more efficient use of drugs.