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Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living‐donor liver transplantation
Author(s) -
Hashida Tohru,
Masuda Satohiro,
Uemoto Shinji,
Saito Hideyuki,
Tanaka Koichi,
Inui Kenichi
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2001.115142
Subject(s) - tacrolimus , cyp3a5 , cyp3a4 , pharmacokinetics , medicine , gastroenterology , confidence interval , trough level , transplantation , calcineurin , liver transplantation , regimen , therapeutic drug monitoring , proportional hazards model , pharmacology , biology , cytochrome p450 , biochemistry , metabolism , genotype , gene
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. Clinical Pharmacology & Therapeutics (2001) 69 , 308–316; doi: 10.1067/mcp.2001.115142