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Lecture-1 The rate determining process To understand the transporter-mediated drug-drug interaction and pharmacogenomics, we have to know the rate determining process of a substrate in the overall clearance. Influx, basolateral efflux, apical excretion, metabolism Summary-1 Genetic polymorphsim (GP) and DDI can affect many processes such as uptake, biliary excretion, sinusoidal efflux and metabolism. Extended “clearance concept” indicates that the rate-determing process of the clearance of drugs from the blood compartment changes depending upon the relative value for each transport and metabolic process. The uptake often governs the overall clearance, and it is the case when the sum of intrinsic clearance of metabolism and biliary excretion far exceeds the sinusoidal efflux clearance. How about in human ? Clinically Relevant Transporter mediated DDI P-gp (mainly in the GI, less in BBB,Liver,Kidney) 　　　　(Because of the low inhibitor conc in the circulating blood) OATP1B1 (Liver) OAT1,OAT3, OCT2 (Kidney) PEPT1 (GI) Except in the GI, little is known about the clinical relevance of ABC transporter mediated DDI (MDR1,BCRP,MRP2,MRP3,MRP4,MRP5) What should we have achieved 10 years laterin the transporter research field? References Giacomini KM., Sugiyama Y, 2005. Membrane transporter)s and drug response. In: Goodman Gilmans The Pharmacological Basis of Therapeutics, edited by Laurence L. Brunton, Brunton L. 11th Edition, McGraw-Hill Professional, New York, pp. 41-70. Sugiyama Y. :Druggability: selecting optimized drug candidates Drug Discovery Today (editorial) 10: 1577-1579 (2005) Shitara Y, Horie T and Sugiyama. Y : Transporters as a determinant of drug clearance and tissue distribution Eur J Pharm Sci., 27: 425-446 (2006) Maeda K. and Sugiyama Y. In vitro-In vivo Scale-up of Drug Transport Activities. In: ”Drug Transporters” pp. 557-588, ed. by You G. and Morris M.E., Wiley Interscience, 2007. Kusuhara H and Sugiy