Under the influence of the modern life styles, diseases show a tendency of becoming complex and chronic. As a result, long term medical intervention has also become inevitable. In the treatment of patients, the risk of therapeutic failure or poor control of the disease is present. This is because in addition to the drug side effects that will also be experienced by a healthy person who received similar drug treatment, the pathological state of a disease may evoke unexpected drug effects can be classified into two category, namely, a consequence of altered pharmacodynamics, i.e. change in target protein sensitivity; and a consequence of altered pharmacokinetics, i.e. change in absorption, distribution, metabolism, and excretion of the drug. Hence, needless to say that a thorough understanding of the drug pharmacokinetics under different disease states is extremely important.
In chronic renal failure patients, uremic toxins which are harmful metabolites, have been found to accumulate to a high degree in occurrence of the uremic plasma. In order to overcome the complication that inhibits the QOL of dialysis patients, to prevent the adverse effects of drugs in chronic renal failure patients, it is necessary to clarify the interaction mechanism between biogenic molecule and uremic toxins.
　Recently, we have reported that uremic toxins such as indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indoleacetate and hippurate play an important role in the inhibition of serum protein binding of drugs in chronic renal failure. In addition, we have shown in pharmacokinetic analysis using rats that, these uremic toxins are mainly eliminated from plasma via active tubular secretion of the kidney. Subsequently, rat organic anion transporter 1 (rOat1) and rOat3 have been shown to involve in their uptake on renal basolateral membrane of the proximal tubules using stable transfectants of rOat1, rOat3 and rat kidney slices. In addition, human OAT1 (hOAT1) and hOAT3 have also shown to involve in the renal uptake of uremic toxins. Recent findings suggest that uremic toxins promote the progression of renal failure by damaging tubular cells . Consequently, increased concentrations of uremic toxins in the renal tubules would exacerbate the deterioration of renal function in chronic renal failure, suggesting that OATs-mediated uptake of these toxins lead to further loss of nephrons.
　At present, we are attempting to predict the pharmacological alteration of drugs and expression mechanism of uremic syndrome from the pharmacokinetic properties of uremic toxins and pathophysiological condition of the patient. Research projects of the following topics are currently underway:

Analysis of the Factors Influencing Drugs Pharmacokinetics in Disease State and Their Clinical Relevance

　1. Molecular Mechanisms of the Tissue Distribution Properties of Uremic Toxins　

　2. Functional and Molecular Characterization of Drug Transporters in Disease State

　3. Clinical Therapeutic Strategy Utilizing the Drug-Drug Interaction Phenomena

　4. Stereoselectivity in the Pharmacodynamics

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