Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation.
BACKGROUND
Living-donor liver transplantation (LDLT) and subsequent immunosuppressive therapy with tacrolimus have been cornerstones in the recovery of patients from end-stage liver failure, but there has been no critical dosage regimen for tacrolimus therapy, especially the initial dosage. In this study, we examined whether the absorptive barriers, multidrug resistance protein (MDR1), or cytochrome P450 IIIA4 (CYP3A4) are important pharmacokinetic factors for tacrolimus and are prognostic indicators for LDLT outcome.


METHODS
We used competitive polymerase chain reaction to evaluate the messenger ribonucleic acid (mRNA) expression levels of MDRL And Cyp3A4 in mucosal cells of the upper jejunum from a part of the Rroux-en- Y limb for biliary reconstruction during LDLT of recipients (n = 48). The tacrolimus dosage was started at an oral dose of 0.075 mg/kg every 12 hours and adjusted on the basis of its whole-blood trough level by use of a semiautomated microparticle enzyme immunoassay.


RESULTS
The mRNA expression level of MDR1 (r = -0.776), but not CYP3A4 (r = -0.094), was inversely related to the concentration/dose ratio of tacrolimus. High levels of MDR1, but not CYP3A4, were strongly associated with reductions in survival rates after LDLT with the Kaplan-Meier method and log-rank statistics (P =.020 and P =.135, respectively). With use of a Cox regression procedure, high levels of MDR1 (relative risk, 12.99; 95% confidence interval, 1.64-103.23), but not CYP3A4 (relative risk, 0.93; 95% confidence interval, 0.87-1.00) appeared to be a significant prognostic indicator for poor survival.


CONCLUSIONS
Intestinal MDR1 is not only a good probe with which to predict the interindividual variation in tacrolimus pharmacokinetics after LDLT but also a powerful prognostic indicator for the outcome of LDLT.
Hashida
T
T
Department of Pharmacy, Kyoto University Hospital, and the Faculty of Medicine and the Department of Transplantation and Immunology, Graduate School of Medicine Kyoto University, Japan.
Masuda
S
S
Uemoto
S
S
Saito
H
H
Tanaka
K
K
Inui
K
K
D000293:Adolescent; D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D005260:Female; D019450:Genes, MDR / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D007422:Intestines / Q000276:immunology*; D017093:Liver Failure / Q000401:mortality / Q000628:therapy*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016019:Survival Analysis; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus