| Objectives:Tacrolimus(TAC)is a commonly used immunosuppressant in clinical practice.The safe and effective range of its blood concentration which with great individual differences and many influencing factors is narrow.Tacrolimus and proton pump inhibitors(PPI)are often used in combination after kidney transplantation.However,regarding the effect of PPI on the blood concentration of tacrolimus,and whether the effect is related to gene polymorphism,the current research conclusions were controversial.This study will preliminary analyze the relationship between trough blood concentration/daily dose(C0/D)of TAC with omeprazole,pantoprazole,and to explore the effect of co-administration of PPI on the Co/D of tacrolimus in patients with different genotypes retrospectively,so as to provide reference for the individualized of tacrolimus.Method:A total of 192 patients who underwent kidney transplantation in the First Affiliated Hospital of Kunming Medical University from October 2013 to July 2020 were enrolled and divided into omeprazole group(92 cases)and pantoprazole group(100 cases)according to the type of PPI used during early postoperative hospitalization.The blood concentration of tacrolimus was determined by enzyme multiplied immunoassay technique,after extracting the blood DNA of the patients,the SNaPshot detection method was used to determine CYP2C19*2(rs 4244285),CYP2C19*3(rs 4986893),CYP2C19*17(rs 12248560),CYP3A5*3(rs 776746),CYP3A4*1G(rs 2242480)genotypes.All data was analyzed by paired t-test or Wilcoxon signed rank test after the normality text was finished by the method of Shair-Wilk test.1.In order to investigate whether OMP or PPZ affects the C0/D of TAC,a paired comparison of the C0/D during the period of co-administration and discontinuation of PPI was performed.2.Multiple linear regression was used to analyze the correlation between OMP or PPZ,genotype,Hemoglobin in Blood(HGB)and other indicators with C0/D.3.In order to further investigate whether PPI affects Co/D of TAC in the patients with different genotypes,a paired comparison of the C0/D in patients with same genotype during the period of co-administration and discontinuation of PPI was performed.Results:1.The effect of co-administration of OMP and PPZ on the C0/D of TAC:①OMP group:there was no significant difference in C0/D of TAC during the period of co-administration and discontinuation of OMP(p>0.05).②PPZ group:The C0/D of TAC during the co-administration of PPZ was lower than the C0/D during the discontinuation of PPZ(p<0.05).2.Multiple linear regression analysis results show that there was no correlation between co-administration or discontinuation of OMP with C0/D of TAC,while co-administration or discontinuation of PPZ was related,excepting weight,HGB,the patient’s CYP3A5 and CYP3A4 metabolic phenotypes related to C0/D of TAC(p<0.05).3.Effects of co-administration of OMP or PPZ on C0/D of TAC in patients with different metabolic phenotypes:①Stratified analysis based on CYP2C19 metabolic phenotypes:OMP group:There was no significant difference in Co/D of TAC during CYP2C19 all different metabolizer during the co-daministration and discontinuation of OMP(p>0.05).PPZ group:In patients with CYP2C19 extensive metabolizer,the C0/D of TAC during the co-administration of PPZ was lower than that during the discontinuation of PPZ(p<0.05).There was no significant difference in C0/D of TAC in patients with other metabolizer during co-administration and discontinuation of PPZ(p>0.05).②Stratified analysis based on CYP3A5 metabolic phenotypes:OMP group:There was no significant difference in C0/D of TAC in CYP3A5 all different metabolizer during the co-administration and discontinuation of OMP(p>0.05).PPZ group:In patients with CYP3A5 poor metabolizer,the C0/D of TAC during the co-administration of PPZ was lower than that during the discontinuation of PPZ(p<0.05).There was no significant difference in C0/D of TAC in patients with extensive metabolizer during co-administration and discontinuation of PPZ(p>0.05).③Stratified analysis based on CYP3A4 metabolic phenotypes:OMP group:There was no significant difference in C0/D of TAC in CYP3 A4 all different metabolizer during the co-administration and discontinuation of OMP(p>0.05).PPZ group:In patients with CYP3A4 poor metabolizer,the C0/D of TAC during the co-administration of PPZ was lower than that during the discontinuation of PPZ(p<0.05).There was no significant difference in C0/D of TAC in patients with extensive metabolizer during co-administration and discontinuation of PPZ(p>0.05).④Stratified analysis based on the combination of CYP2C-9 and CYP3A5 metabolic phenotypes:OMP group:In patients among all combinations of CYP2C19 and CYP3A5 metabolic phenotypes,there was no significant difference in C0/D of TAC during co-administration and discontinuation of OMP(p>0.05).PPZ group:In patients with CYP2C19 extensive metabolizer CYP3A5 poor metabolizer,the C0/D of TAC during the co-administration was lower than that during discontinuation of PPZ(p<0.05),there was no significant difference in C0/D of TAC in any other combinations of CYP2C19 and CYP3A5 metabolic phenotypes during the co-administration and discontinuation of PPZ(p>0.05).Conclusions:1.Weight,HGB,CYP3A5 and CYP3A4 metabolic phenotypes were correlated with C0/D of tacrolimus.2.There was no correlation between co-administration or discontinuation of OMP with C0/D of TAC,and the combined use of OMP in patients with different metabolic genotypes had no significant effect on C0/D of TAC.However,further research with expanded sample size is needed.3.Co-administration or discontinuation of PPZ was related to the Co/D of TAC,but there were individual differences,The combined use of PPZ made a lower C0/D in patients with CYP2C19 extensive metabolizers,CYP3A5 and CYP3A4 poor metabolizers.However,further research with expanded sample size is needed,especially make a verification in patients with special genotypes. |
PDF Full Text Request