Study On The Regularity Between Cyp3a5/3a4/3 Ap1 Polymorphism In Donors/recipients And Mediccation Of Tacrolimus After Liver Transplantation

Objectives:To investigate the regularity between the genetic factors of donors/recipients and the medication of FK506 in liver transplantation recipients in the first 6 month post-transplantaton,and determine the appropriate dosage of FK506 in patients with different phenotypes at different stage after transplantation.Methods:This study include two parts:the first part,70 liver transplantation recipients were prospectively involved in this study,and the blood samples of each donor and recipient were collected.The dose(D)and C0 of FK506,the weight,drug co-administration,and the relevant clinical index were detected and recorded at 7,14,21,28day and 2,3,6month.The C0 was detected by chemiluminescence Microparticle Immuno Assay(CMIA),and the polymorphism of CYP3A5*3,CYP3A4*18B,CYP3AP1 was detected by DNA direct sequencing.Stepwise regression analysis was used to investigate the regularity of genetic factors in donors and recipients affect the individualized medication of FK506 with the time after transplantation.And then on the basis of this,the recipients were grouped according to different gene types which was involved in each regression equation,so the patients were grouped by CYP3A5*3 in recipients at the 7day,CYP3A5*3 both in donors and recipients at the 14,21,28day,and the CYP3A4*18B,CYP3AP1,CYP3A5*3 in donors at the 2,3,6 month individually,and the C0/D of FK506 in different groups was compared.The second part,which is on the basis of the first part,110 liver transplantation patients were involved in this study,the dose and C0 of FK506,the weight,drug co-administration,and relevant clinical index were detected and recorded at 7,14,21,28 day and 2,3,6month.Also the polymorphism of CYP3A5*3,CYP3A4*18B,CYP3AP1 in donors and recipients was detected.Which is most different from the first part is that the three gene types were considered together as phenotype.So the 110 patients were grouped by the CYP3A5-CYP3A4-CYP3AP1 phenotype of the recipients at the 7 day,this phenotype of both donors and recipients at the 14,21,28day,and also this phenotype only in donors at the 2,3,6 month,and the C0,D,C0/D of FK506 was compared in different groups.Results:The first part:according to the results of stepwise regression analysis,which will significantly influence the individualized medication of FK506 is the genetic factors,and it is changed with time.The regularity is that the gene types only in the recipients at the 7day,the gene types both in donors and recipients at the 14,21,28day,and then the gene types only in donors at 2,3,6month were the most important factors which will influence the C0/D of FK506.And then the patients were grouped by different gene types,the result is that the C0/D of the slow metabolism group(CYP3A5 GG in recipients)is 1.5 times to the quick metabolism group(CYP3A5 AA in donors)at the 7day,and the C0/D of the slow metabolism group(CYP3A5 GG in donors and recipients)is about 2 times to the quick metabolism group(CYP3A5 AA/AG in donors and recipients)at the 14,21,28day.The C0/D of slow metabolism groups(CYP3A4 GQ CYP3AP1 AA,CYP3A5 GG in donors individually)and middle metabolism(CYP3A4 AG,CYP3AP1 AG,CYP3A5 AG in donors individually)are at the 2,3,6month are:120±73.4vs72.9±39.3(2month,1.6times);160± 113vs78.4± 51.0(3month,2times);178± 95.2vs78.9± 36.7(6month,2.3times),(P<0.05).The second part:on the basis of the first part,the patients were grouped by CYP3A5-CYP3A4-CYP3AP1 phenotype in donors or recipients at different time after transplantation.The C0/D of the slowest and quickest metabolism group is:136±110vs65.9±25.9(7day,1.6times);131±107vs50.1±18.9(14day,2.6times);129±84.8vs51.7± 18.3(21day,2.5times);162±89.2vs65.9±21.0(28day,2.5times),137±75.4vs71.9±38.1(2month,2times);143±82.5vs75.8±52.4(3month,2times);207±102vs77.1±38.7(6month,2.7times).And the C0/D of the patients with same phenotype will asend with time.Conclusions:1.The genetic factors are the most important reasons for the individual diference of the FK506 C0/D,and it is changed with time.The regularity is:recipients(7day post-transplantation)→donors and recipients(14,21,28 day)→donors(2,3,6month),which can explain the dose of some patients will change significantly at different stage post-transplantation.2.It is more powerful evaluating the CYP3A5-CYP3A4-CYP3AP1 phenotype rather than just any one gene type in donors or recipients,which indicate that the individualized medication should be realized by considering these three gene types together.3.The C0/D of the patients with same gene type will ascend with time,but it is not significant,which indicate that it is stable if the individualized medication.