A Clinical Pharmacogenetics Study On OATP1B1 & AML

The different response to drugs and other xenobiotics among individuals and the susceptibility to almost all diseases are to some extent due to variations in human genome.In the past 40 years,driven by the advances in molecular biology,pharmacogenetics has evolved from a minor discipline to a major driving force of clinical pharmacology. Nowadays,over 10 million SNPs and other kinds of variants have been detected in human genome.If the budget is enough,we can assess more than 1 million polymorphisms or the expression of more than 25,000 genes in each clinical study.However,this has not yet changed daily therapeutic mode in clinic which is somehow empirical.But some physicians are aware of the importance of some gene polymorphisms, such as those in CYP2C9,CYP2C19,CYP2D6,TPMT and VKORC1.To more practical situation,pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research.Pharmacognetics displines have become a basic requirement of many large clinical trials on new drugs.The US Food and Drug Administration(FDA) also has encouraged the voluntary deposition of supplementary pharmacogenomics data.Following the International Hunam Genomics Project,International HapMap Project is carried out under the cooperation of scientists coming from US,Japan,Britain,Canada,China and Nigeria.It was launched in 2002 with the aim of providing a public resource to accelerate medical genetic research.The information in this database will be used for genetic studies and clinic studies on phenotyps.In HapMap project,DNA samples retrieved were from 270 donors come from four different places and four different species.With the releasing of PhaseⅡdata,over three million SNPs have been analyzed.All the data have been open to public through internet now.Based on these information,the aim of our study was to clarify the impact of the common genetic polymorphisms occurred on OATP1B1 on the pharmacokinetics of atorvastatin and how does the kinetics of atorvastatin and rosuvastain change when the activity of OATP1B1 is inhibited via a competitive inhibition manner or non-competitive inhibition manner.We also lanched a well designed clinical study which is accomplished in Ulm University,Germany,on the clinical outcome of AML patients to the perspective of Pharmacogenomics with the guide of HapMap knowledge.This project provided new explains for individual differences of drug response and explored a new way to translate HapMap knowledge into the pharmacogenetics and pharmacogenomics study.In this project we have found that:1.OATP1B1 haplotypes significantly changes the pharmacokinetics of atorvastatin in vivo.2.OATP1B transporters represent the major hepatic uptake systems for atorvastatin.Single oral dose of 600mg rifamin can significantly inhibit the hepatic uptake of atorvastain.OATP1B1 haplotypes significantly influence the inhibition effect of rifampin on the activity of OATP1B1. Individuals with OATP1B1~*1a/~*1a wild type were more sensivie to the inhibition of rifampin than OATP1B1~*5 carriers.3.Confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1αin vivo.4.Frequencies of several SNPs of hCNT1,CDA and dCK are different between AML patients and healthy individuals.In RD and ED group, bone marrow transplantation and the use of ATAR can improved the prognosis of AML patients,hCNT1 genetic variat,1561C＞T(rs2242046), was associated with drug toxicity and overall survival rate in patients who were complete remission.5.The PhaseⅡdatabase released in HapMap provides aboundant and confidential information for the analysis of dCK genome.Using HapMap database can provide a new method for pharmacogenetics and pharmacogenomics research.In summary,we studied the inter-individual difference of atorvastatin response to the perspective of pharmacogentics and drug interactions of atorvastatin and rosuvastain.We also explored the impact of genetics variants involved in cytarabine metabolism on the clinical outcomes of AML patiens and for the first time translate the HapMap knowledge into clinical study which provides a new approach to proceed with pharmacogenetics and pharmacogenomics study.