Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation

Background. Living-donor liver transplantation (LDLT) and subsequent immuno suppressive therapy with tacrolimus have been cornerstones in the recovery of patients from end-stage liver failure, but there has been no critical do sage regimen for tacrolimus therapy, especially the initial dosage. In this study, we examined whether the absorptive barriers, multidrug resistance p rotein (MDR1), or cytochrome P450 IIIA4 (CYP3A4) are important pharmacokine tic factors for tacrolimus and are prognostic indicators for LDLT outcome. Methods: We used competitive polymerase chain reaction to evaluate the mess enger ribonucleic acid (mRNA) expression levels of MDR1 and CYP3A4 in mucos al cells of the upper jejunum from a part of the Roux-en-Y limb for biliary reconstruction during LDLT of recipients (n = 48). The tacrolimus dosage w as started at an oral dose of 0.075 mg/kg every 12 hours and adjusted on th e basis of its whole-blood trough level by use of a semiautomated micropart icle 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 tacroli mus. High levels of MDR1, but not CYP3A4, were strongly associated with red uctions in survival rates after LDLT with the Kaplan-Meier method and log-r ank statistics (P =.020 and P =.135, respectively). With use of a Cox regre ssion 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 bu t also a powerful prognostic indicator for the outcome of LDLT.