| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2004: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2003: ¥8,300,000 (Direct Cost: ¥8,300,000)
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| Research Abstract |
Drug toxicity is a significant problem in developing drugs, because the toxicity induced by drugs or drug candidates will lead to the removal from the market or termination of drug development, even though the compound exhibits excellent pharmacological effect.
To evaluate possible toxicity of drugs or drug candidates, it will be essential to accumulate more information on the mechanisms of occurrence of drug-induced toxicity. As one of possible mechanisms, transporter proteins should be involved, because transporters significantly affect the cellular concentration and the pharmacokinetic profiling of drugs. Here, we studied the transport mechanisms of drugs by focusing on several tissues, including intestine, liver, kidney, brain, testis, tumor, and blood cells. As the results, we succeeded to identify SLCO2B1(OATP-B) as the transporter involved in intestinal absorption of anionic drugs, in functionally pH dependent manners. Furthermore, we studied the brain penetration of H1-antagonists and the permeability of the drug across the blood-brain barrier was strictly regulated by transporters like P-glycoprotein and molecularly-unknown cation transporters. In the case of kidney, apically and basolaterally expressed transporters like OCTs and OCTNs were studied and their pharmacological relevance was suggested. Next, we evaluated the effect of genetic polymorphisms of transporter genes on the transport activity. SLCO1B1(OATP-C) is a hepatic transporter important for hepatic uptake of drugs and the genetic variants OATP-C^*15 exhibited lowered transport activity than wild one for toxicologically important drugs like troglitazone, irinotecan and others. Furthermore, we studied the regulation mechanism of the gene expression of hepatic transporters by focusing on nuclear receptor FXR. These studies clarified that there are many factors that affect apparent activity of transporter and we need to study further the clinical.
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