Effect Of CYP3A5 Gene Polymorphism On Concentration,Efficacy And Adverse Reactions Of Tacrolimus In Patients With Idiopathic Membranous Nephropathy

Objective:To explore the effect of CYP3A5*3 polymorphism on Tacrolimus concentrations,efficacy,and adverse reactions in idiopathic membranous nephropathy.Methods:Forty-five patients with idiopathic membranous nephropathy who were underwent methylprednisolone and tacrolimus were enrolled in this study.The patients were divided into three groups（AA,AG,and GG）according to their CYP3A5 genotype.Concentration,daily dosage,concentration/dose（C₀/D）ratio of tacrolimus were tested 1week,2 weeks,1 month after medication respectively.Complete blood count,biochemical routine,and 24-hour urine protein were tested at 1week,2 weeks,1 month,2 months,3 months,6 months,9 months,12months after medication respectively.Adverse reactions were recorded at each time point as well.Clinical eficacy was analysised and evaluated.Analysis and evaluated clinical efficacy of the three groups.Results:1 Genotype distributionA total of 45 patients were screened for genotype,among which 6patients with AA genotype（CYP3A5*1/*1）,accounting for 13.3%;19patients with AG genotype（CYP3A5*1/*3）,accounting for 42.2%;20patients with GG genotype（CYP3A5*3/*3）,accounting for 44.5%.2 Comparison of medication dose among three groupsThere were no significant differences among AA genotype group,AG genotype group,and GG genotype group at different periods（P>0.05）.3 Comparison of tacrolimus concentration among three groupsCompared with the AA genotype group,the concentration of AG genotype group was significantly increased at 1 and 2 weeks after medication（P<0.05）;although the concentration of AG genotype group after the medication of 1 month was higher than that of AA genotype group,but the difference was not statistically significant（P>0.05）;the concentration of GG genotype group were markedly increased at 1 week,2weeks,and 1 month after the medication（P<0.05）.Compared with AG genotype group,the concentration of GG genotype group were significantly nincreased at 1 week,2 weeks,and 1 month after the medication（P<0.05）.4 Comparison of C₀/D ratios among three groupsThe C₀/D ratio of three groups after the medication at 1 week,2weeks,1 month were as follows:AA genotype group<AG genotype group<GG genotype group（P<0.05）.5 Comparison of efficacy among three groupsThe efficacy of GG genotype group was significantly higher than that of AA genotype group（Bonferroni correction,P<0.0167）.However there was no significant difference in the efficacy between GG and AG genotype group,or between AG and AA genotype group（Bonferroni correction,P<0.0167）.6 Comparison of remission cases and non-remission casesRemission cases（complete remission cases and partial remission cases）had significantly higher average serum concentrations（C₀）and average concentration/dose（C₀/D）than non-remission cases（non-remission cases and relapse cases）respectively（P<0.01;P<0.05）.7 Comparison of adverse reactions among three groupsAdverse reactions were found in 29 of the 45 patients.The incidences of adverse reactions in GG genotype group,AG genotype group,and AA genotype group were 33.3%,52.6%,and 85%respectively.The incidence of adverse reactions among the three genotypes was statistically significant（P<0.05）.The incidence of adverse reactions in GG genotype group was significantly higher than that of AA genotype group（Bonferroni correction,P<0.0167）.However,there was no significant difference in the incidence of adverse reactions between GG and AG genotype group,or between AG and AA genotype group（Bonferroni correction,P>0.0167）.Patients with adverse reactions had higher C₀and higherC ₀/Dand lower triglycerides than those without adverse reactions（P<0.05）.Conclusions:1 CYP3A5*3 polymorphism affects tacrolimus concentration and C0/D,and GG group is superior to AG group and AA group.In order to achieve some certain concentration,tarcrolimus dose should be tailored with different genotypes.Generally the dose of allelic gene is AA genotype>AG genotype>GG genotype.2 GG genotype patients are more likely to achieve remission and have adverse reactions than AA genotype patients.Patients with high concentrations and C₀/D are more likely to achieve remission and have adverse reactions.Patients with low triglycerides are more likely to have adverse reactions.3 Patients with idopahtic membranous neohropathy should have their CYP3A5 genotype tested before tacrolimus medication.This can help doctors make accurate decision to maintain tacrolimus concentration within a reasonable range,thus ensure the effectiveness and safety of the treatment.