Analysis Of Influencing Factors Of Imatinib Plasma Concentration And Association With SLC22A1 Gene Polymorphism

Objective Gastrointestinal stromal tumors(GIST)are the most common mesenchymal tumors of the digestive tract.Imatinib mesylate is a first-line treatment of high-risk GIST,which can significantly improve patient survival and prolong progression-free survival.B2222 clinical retrospective study suggests that patients with imatinib concentration(Cmin)>1100 ?g/L can benefit significantly;a clinical study in France suggests that imatinib Cmin concentrations of 760?g/L can be considered appropriate and effective treatment value.The plasma concentration of imatinib is closely related to the survival and progression of progression-free disease.However,the plasma concentration of imatinib inner-patient and inter-patients variation is large and various of factors can lead to different concentrations of imatinib plasma.So long-term monitoring of blood concentration is necessary,but the current study's results are different,and still lack of Chinese blood concentration monitoring of large-scale effective data.Above all,this study will take a large-scale imatinib plasma concentration monitoring in GIST patients who take the imatinib,analysis of its related factors and single nucleotide polymorphisms between the links,for further identification Chinese people methotrexate imatinib effective treatment of the concentration of the window lay the foundation.This study has important clinical and scientific valve.Methods Blood samples were collected from the last drug taking time(24 ± 2)h,centrifuged in vitro for 5 hours,and plasma was analyzed by high performance chromatography-mass spectrometry(LC-MS / MS).After centrifugation,the results were analyzed by Graph Pad prism 6.0 and SPSS 13.0 software.The results were expressed as mean ± standard deviation,and the Snapshot was used to analyze the SNP polymorphism.T-test was used to analyze the difference between the two groups.ANOVA was used to analyze the difference between the multiple groups.Results 1.135 cases GIST patients plasma who are take imatinib 4 weeks or more regularly,of which the primary tumor in the stomach 68 cases,52 cases of small intestine,16 cases of other parts;the occurrence of liver metastases in 17 cases,abdominal pelvic metastasis in 3 cases;medication Dose: 400 mg / d in 125 cases,300 mg / d in 7 cases,600 mg / d in 4 cases;risk classification: 39 cases of medium-risk patients,97 cases of high-risk patients.2.LC-MS/MS method was used to confirm the specificity,precision,accuracy and stability.The standard curve and the lower limit of detection were in accordance with the testing requirements.3.The plasma concentration of imatinib mesylate(400mg /d)and body surface area(p= 0.0356,R2=0.035),creatinine clearance(p=0.0443,R2 =0.072)was negative correlation,and the plasma concentration of imatinib mesylate(400mg /d)and age,leukocyte cell count,albumin count,liver transaminase was no related(p> 0.05).4.Different surgical methods,medication during the daily defecation frequency will lead to different plasma concentrations(400mg / d)(p<0.05),and whether the edema or liver metastases occurred during the medication do not influence the drug concentration(p > 0.05).5.ABCB1 rs1045642,ABCB1 rs1128503,ABCG2 rs2231137,SLC22A1rs2282143,CYP3A5*3 rs776746 polymorphisms were not associated with plasma concentration(p> 0.05).SLC22A1 rs628031 polymorphism had an effect on plasma concentration(p<0.05).The plasma concentration of GG allele was significantly lower than that of AG allele(p<0.05),and there was no significant difference in plasma concentration between AAand GG/AG allele(p> 0.05).Conclusion 1.LC-MS / MS method for the detection of imatinib plasma concentration has a good accuracy and repeatability;2.Imatinib plasma concentration and body surface area,creatinine clearance was negatively correlated;3.Gastric surgery patients than other patients with low blood concentration should be lower;daily excessive number of defecation will affect the drug concentration;4.SLC22A1 rs628031 polymorphism will have an impact on imatinib plasma concentration;GG allele plasma concentration was lower than AG allele plasma concentration.