| Objective:(1)To explore the indications for renal transplant recipients who were switched from Cyclosporine A(Cs A)to tacrolimus(TAC).(2)To study the impact of CYP3A5,CYP3A4 and ABCB1 genetic polymorphisms on the initial dosage regimen of TAC in renal transplant recipients who were conversed from Cs A to TAC.(3)To explore the effects of PXR,POR and VDR which are the upstream regulatory genes of CYP3A5,CYP3A4 and ABCB1 on the initial dosage regimen of TAC in renal transplant recipients who were conversed from Cs A to TAC.Ultimately,to provide reasonable reference for personalized TAC treatment regimen in renal transplant recipients who may switch immunosuppressant from Cs A to TAC.Methods:(1)The clinical follow-up data of 92 renal transplant recipients switched from Cs A to TAC were collected.The clinical therapeutic outcomes of AR and DIDs induced by Cs A were analyzed during the first year after conversion from Cs A to TAC using SPSS17.0 software.(2)Polymerase Chain Reaction-Restriction Fragment Length Polymorphism(PCR-RFL P)was employed to investigate CYP3A5*3A6989G,CYP3A4*1GA392G,ABCB1C1236 T,ABCB1G(A)2677T,ABCB1C3435 T,PXRG7635A,POR*28C1508T,VDRFok I C>T,VDRBsm I A>G,VDRApa I G>T and VDRTaq I T>C genotype data.(3)Allele,genotype frequencies,haplotype and Hardy-weinberg equilibrium were tested by SHEsis software.(4)The impact of CYP3A5*3,CYP3A4*1G,ABCB1,PXR,POR*28 and VDR genetic polymorphisms on the C0/D of Cs A and TAC were retrospectively analyzed in renal transplant recipients conversed from Cs A to TAC using SPSS17.0 software.Results:(1)Compared to before conversion,the levers of Scr and BUN were signifcantly decreased in 1,3,6 and 12 months after conversion for renal transplant recipients with CScr or AR(P<0.05 or 0.01).The levers of direct bilirubin(DB)and total bilirubin(TB)were also signifcantly decreased(P<0.05 or 0.01)in 1,3,6 and 12 months for drug-induced liver injury(DILI)recipients.And the ALT average lever was signifcantly decreased in 12 months after conversion(P<0.05).The serious complications of gingival hyperplasia(GH)were usually stopped by TAC after conversion.However,the levers of fasting blood glucose(FBG)were significantly increased in 12 months after conversion(P<0.05).(2)CYP3A5*3 genetic polymorphism did not affect the C0/D of Cs A on day 0,but it affected the C0/D of TAC after conversion from Cs A to TAC.When the D of TAC in CYP3A5*3AA group was 1.71 fold that of CYP3A5*3AG group(P=0.000)and 3.0 fold that of CYP3A5*3GG(P=0.021),the C0 of TAC in diffident CYP3A5*3 genotypes reached the same target blood concentrations [(5.77±1.70 ng/ml)vs(5.65±1.28 ng/ml),P=0.874;(5.77±1.70 ng/ml)vs(6.09±1.12 ng/ml,P=0.245].And the C0/D of TAC in CYP3A5*3AA,AG and GG genotypes were significantly different [(50.59±3.40 ng·kg/ml/mg/day)vs 80.71(64.66-98.65)ng·kg/ml/mg/day,P=0.021;(50.59±3.40 ng·kg/ml/mg/day)vs 116.16(110-264.53)ng·kg/ml/mg/day,P=0.006].(3)CYP3A4*1G genetic polymorphism did not affect the C0/D of Cs A and TAC after conversion from Cs A to TAC(P>0.05);CYP3A5*3-CYP3A4*1G haplotypes affected the C0/D of TAC after conversion.When the D of TAC in CYP3A5*3AA-CYP3A4*1GAA group was 1.57 fold that of CYP3A5*3AG-CYP3A4*1GAG group(P=0.047)and 2.75 fold that of CYP3A5*3GG-CYP3A4*1GGG(P=0.001),the C0 of TAC in diffident CYP3A5*3-CYP3A4*1G Homozygous haplotypes reached the same target blood concentrations[(5.30±2.12 ng/ml)vs(5.70±1.41 ng/ml),P=0.683;(5.30±2.12 ng/ml)vs(6.14±1.08 ng/ml,P=0.396].And the C0 /D of TAC in CYP3A5*3AA-CYP3A4*1G AA,AG-AG and GG-GG haplotypes were significantly different[(51.14±4.61 ng·kg/ml/mg/day)vs 80.17(70.72-95.07)ng·kg/ml/mg/day,P=0.032;(51.14±4.61 ng·kg/ml/mg/day)vs 117.15(110.83-254.49)ng·kg/ml/mg/day,P=0.025].(4)The C0/D of Cs A and TAC were not associated with different ABCB1C1236 T,G(A)2677T and ABCB1C3435 T genotypes and their haplotypes(P>0.05).(5)PXRG7635A genetic polymorphism did not affect the C0/D of Cs A on day 0 after conversion from Cs A to TAC,but it affected the C0/D of TAC after conversion.When the D of TAC on day 28 in AA group was 0.57 fold that of AG group(P=0.030)and 0.57 fold that of GG(P=0.027),the C0/D of TAC in AA,AG and GG genotypes were significantly different[(180.93±99.38 ng·kg/ml/mg/day)vs 81.25(62.49-115.68)ng·kg/ml/mg/day,P=0.021;(180.93±99.38 ng·kg/ml/mg/day)vs 94.40(70.08-121.01)ng·kg/ml/mg/day,P=0.037].However,the C0/D of Cs A and TAC were not associated with different PXR genotypes in renal transplant recipients with CYP3A5*3GG,which may be caused by a high degree of linkage disequilibrium(D'=99%)between CYP3A5*3 and PXRG7635 A.(6)POR*28C1508T genetic polymorphism did not affect the C0/D of Cs A and TAC after conversion from Cs A to TAC(P>0.05),but it affected the C0/D of Cs A on day 0 in renal transplant recipients with CYP3A5*3GG.The C0/D of Cs A in CC,CT and TT genotypes were significantly different [(71.59±42.32 ng·kg/ml/mg/day)vs(42.80±10.83 ng·kg/ml/ mg/day),P=0.043;(71.59±42.32 ng·kg/ml/mg/day)vs(36.32±16.27 ng·kg/ml/mg/day),P=0.028].(7)There was no association between VDR genetic polymorphism(including VDRFok I C>T,VDRBsm I A>G,VDRTaq I T>C and VDRApa I G>T)and the C0/D of Cs A and TAC after conversion from Cs A to TAC(P>0.05).But VDRBsm I A>G significantly affected the C0/D of TAC on day 14,21 and 28 in renal transplant recipients with CYP3A5*3GG(P<0.05).Conclusion:(1)For the renal transplant recipients with normal blood sugar,if they have suffered from AR or the serious DIDs of CScr,DILI and(or)GH induced by Cs A,conversion from Cs A to TAC should be considered and might be benificial to improve the quality of life.(2)The appropriately initial dosage regimen of TAC should be selected according to CYP3A5*3 or CYP3A5*3 combinated with CYP3A4*1G genotype in renal transplant recipients who will converse immunosuppressant from Cs A to TAC.Those recipients who carry CYP3A5*3AA,AG and GG genotypes should be given the TAC D of 0.11~0.12,0.07 and 0.04 mg/kg/day.And then adjust the D of TAC according to the TDM results.(3)PXRG7635A and VDRBsm IA>G were closely related to the metabolism of TAC in renal renal transplant recipients conversed from Cs A to TAC,Which may be used to optimize the TAC dosage regimen established on the basis of CYP3A5*3 and CYP3A4*1G. |
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