Long-Term Influence of CYP3A5 Gene Polymorphism on Pharmacokinetics of Tacrolimus and Patient Outcome After Living Donor Liver Transplantation.
BACKGROUND
We investigated a long-term association between donor/recipient CYP3A5 polymorphisms, pharmacokinetics of tacrolimus, and recipient outcomes in settings of living donor liver transplantation (LDLT).


METHODS
From February 2002 to November 2009, 67 couples of donor/recipients with tacrolimus administration, who could be genotyped for CYP3A5*3 and *1, were eligible in this study. We compared the dose-adjusted trough levels (C/D ratio) and dose/weight ratio of tacrolimus at 1 to 36 months postoperatively and recipient prognosis according to donor/recipient CYP3A5 polymorphisms; *1*1 in 7, *1*3 in 15, and *3*3 in 45, based on recipient genotype, and *1*1 in 1, *1*3 in 28, and *3*3 in 38, based on donor genotype.


RESULTS
On the basis of the data from C/D ratio and dose/weight ratio of tacrolimus, the recipients who had *1 allele and/or whose donor had *1allele required significantly high doses of tacrolimus with, compared with those without, all through 3 years after transplantation. These data allowed us to show the importance of not only recipient CYP3A5 polymorphisms but also donor polymorphisms to obtain the target tacrolimus blood concentration. The overall survival rates of the recipients with *1*1 (5-year survival rate: 28.6%) were significantly unfavorable, which might have been caused by over-immunosuppression, compared with those with *1*3 (5-year survival rate: 78.8%) and *3*3 genotype (5-year survival rate: 84.3%).


CONCLUSIONS
Immune suppressive therapy with the use of tacrolimus should be tailored on the basis of CYP3A5 genotype, which may reduce the adverse effects and improve graft outcome.
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
H
H
Kato
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan. Electronic address: m-usui@clin.medic.mie-u.ac.jp.
M
M
Usui
Department of Pharmacy, Mie University Hospital, Mie, Japan.
Y
Y
Muraki
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
A
A
Tanemura
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
Y
Y
Murata
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
N
N
Kuriyama
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
Y
Y
Azumi
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
M
M
Kishiwada
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
S
S
Mizuno
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
H
H
Sakurai
Department of Pharmacy, Mie University Hospital, Mie, Japan.
M
M
Okuda
Department of Clinical Laboratory Medicine, Mie University Hospital, Mie, Japan.
K
K
Nakatani
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
S
S
Isaji
D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D017093:Liver Failure / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D016559:Tacrolimus / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus