Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients.
OBJECTIVE
The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype.


METHODS
Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program.


RESULTS
CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5*1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17-1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5*3/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan-Meier method, was significantly associated with the recipient's but not donor's CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81).


CONCLUSIONS
These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.
Fukudo
Masahide
M
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan.
Yano
Ikuko
I
Yoshimura
Atsushi
A
Masuda
Satohiro
S
Uesugi
Miwa
M
Hosohata
Keiko
K
Katsura
Toshiya
T
Ogura
Yasuhiro
Y
Oike
Fumitaka
F
Takada
Yasutsugu
Y
Uemoto
Shinji
S
Inui
Ken-ichi
K
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004351:Drug Resistance / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D016031:Liver Transplantation / Q000502:physiology; D019520:Living Donors; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010597:Pharmacogenetics; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
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; D016559:Tacrolimus