|Research and Education
|The pharmacokinetics for various drugs consist of four kinds of processes such as absorption, distribution, metabolism and excretion, and are regulated by various factors including drug transporters. In our laboratory, research projects have been carried out to determine optimal drug therapies in view of pharmacokinetics, having with the theme “laboratory and clinical studies of the pharmacokinetics, effectiveness and toxicity of drugs”. For examples, we have performed functional and molecular characterization of drug transporters expressed in the intestine, kidney and liver, and the establishment of personalized medicine based on the molecular information of drug transporters. Especially, the research on the renal drug excretion has been carried out over 25 years with leading outcomes in this field: i.e., clarification of the transport mechanisms, cDNA cloning of drug transporters, and elucidation of gene regulatory mechanisms for drug transporters and so on. Furthermore, we have expanded research projects to analyze genetic polymorphisms for clinical practice or transcriptional regulatory mechanism of drug transporters, and to identify and analyze H+/organic antiporter in renal proximal tubules and riboflavin transporter.|
We contribute to personalized medicine of immunosuppressant tacrolimus in the living donor liver transplantation (LDLT). It was demonstrated that the intra- and interindividual variability of tacrolimus pharmacokinetics in allograft recipients is related to the intestinal expression level of MDR1 (ABCB1), an active efflux pump located on the intestinal brush-border membranes, and that the intestinal expression level of MDR1 is a part of prognostic factor for acute cellular rejection and mortality as well as a pharmacokinetic factor in recipients of LDLT (Figure 2). In addition, we establish genome-based population pharmacokinetic model requiring additional CYP3A5 polymorphism and MDR1 mRNA level for individualizing the dosage regimen of tacrolimus in de novo pediatric LDLT recipients. The information is utilized for the determination of the initial dosage regimen for LDLT recipients.
Recently, we investigate the personalized medicine of anticancer drugs. To improve safety and efficiency of chemotherapy, we attempt to identify the factors affecting inter-individual variations of pharmacokinetics or adverse effects of anticancer drugs. The graduate students of Medicine and Pharmaceutical Sciences play pivotal roles for laboratory research, and all members have been tackling with difficult scientific problems from various angles, collaborating with pharmacists in Kyoto University Hospital.
||Yonezawa, A., Inui, K.: Organic cation transporter OCT/SLC22A and H+/organic cation antiporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol., 81(5):563-8. (2011)|
||Toyama, K., Yonezawa, A., Tsuda, M., Masuda, S., Yano, I., Terada, T., Osawa R, Katsura T, Hosokawa M, Fujimoto S, Inagaki N, Inui K.: Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients., Pharmacogenet Genomics., 20(2):135-8. (2010)|
||Terada, T., and Inui, K.: Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem. Pharmacol., 75(9):1689-1696. (2008)|
||Masuda, S., and Inui, K.: An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol. Ther., 112(1):184-198. (2006) [review]|
||Fukudo, M., Yano, I., Masuda, S., Goto, M., Uesugi, M., Katsura, T., Ogura, Y., Oike, F., Takada, Y., Egawa, H., Uemoto, S., Inui, K.: Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin. Pharmacol. Ther., 80(4):331-345. (2006)|