[Factors responsible for inter-individual variations in dosage/concentration of tacrolimus in renal transplant recipients].
OBJECTIVE
To identify the factors responsible for the inter-individual variations in the dosage/concentration of tacrolimus in renal transplant recipients.


METHODS
This study involved renal transplant recipients receiving immunosuppressive therapy with the tacrolimus, mycophenolate and prednisone regimen after the operation. The gender, age, height, body weight, tacrolimus dosage, hormone dosage, diarrhea, blood lipids, liver function, renal function, albumin, and hematocrit of the patients were recorded at different time points, namely in early stage (3, 7, 14, and 30 days postoperatively, 118 cases), at 3 months (103 cases), 6 months (75 cases) and over one year (119 cases) after the operation. The concentrations of tacrolimus and gene polymorphisms at CYP3A5, MDR1 3435, MDR1 2677 and MDR1 1236 were also determined in these patients. Multiple linear regression was used for analysis of these factors with tacrolimus concentration/dosage*body surface area as the independent variable.


RESULTS
Patients in early stage following renal transplantation showed rather poor fitting of the stepwise regression model, which increased obviously 3 months after the operation and further increased till reaching a stable level at 6 months. Multiple factors were found to affect tacrolimus concentration/dosage in the early postoperative stage, during which period these factors underwent drastic variations and became stable 3 months later. In terms of pharmacogenomics, the major factors affecting tacrolimus concentration/dosage included MDR1 3435, MDR1 2677 and MDR1 1236 polymorphisms, which vastly varied between the patients early after the operation. Of these polymorphic sites, CYP3A5 produced only minor effects on tacrolimus concentration/dosage, and was not included as an active factor until the stable phase (over 1 year) following the transplantation; MDR1 3435 was found to be the predominant factor affecting tacrolimus metabolism in the stable phase. Age, liver function, albumin and hematocrit were found to be positively correlated to the independent variable tacrolimus concentration/dosage*body surface area, and identified as important factors responsible for the intra-individual variation of tacrolimus dosage/concentration.


CONCLUSIONS
The variations in the factors affecting tacrolimus dosage/concentration after renal transplantation are consistent with the clinical features of the patients, and these factors vary with the postoperative stages. Pharmacogenomic factors produce the most conspicuous effect on tacrolimus dosage/concentration, and agents that may interfere with tacrolimus metabolism should be avoided after the operation. Age, liver function, albumin and hematocrit are also important factors responsible for the variation of tacrolimus dosage/concentration.
Fu
Shao-jie
SJ
Department of Organ Transplantation,Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. fusaoj@medmail.com.cn
Wang
Yan-bin
YB
Yu
Li-xin
LX
Li
Qiang
Q
Wang
Yi-bin
YB
Xiao
Lu-lu
LL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011184:Postoperative Period; D011241:Prednisone / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D011241:Prednisone; D016559:Tacrolimus