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

Tohru Hashida, Satohiro Masuda, Shinji Uemoto, Hideyuki Saito, Koichi Tanaka, Ken ichi Inui

Research output: Contribution to journalArticle

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Abstract

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 (MDRI), 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 MDR1 and CYP3A4 in mucosal 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 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.

Original languageEnglish
Pages (from-to)308-316
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number5
DOIs
Publication statusPublished - May 1 2001

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Living Donors
Tacrolimus
Cytochrome P-450 CYP3A
Liver Transplantation
Pharmacokinetics
RNA
Confidence Intervals
P-Glycoproteins
Liver Failure
Jejunum
Immunosuppressive Agents
Immunoenzyme Techniques
Cytochrome P-450 Enzyme System
Survival Rate
Extremities
Polymerase Chain Reaction
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation. / Hashida, Tohru; Masuda, Satohiro; Uemoto, Shinji; Saito, Hideyuki; Tanaka, Koichi; Inui, Ken ichi.

In: Clinical Pharmacology and Therapeutics, Vol. 69, No. 5, 01.05.2001, p. 308-316.

Research output: Contribution to journalArticle

Hashida, Tohru ; Masuda, Satohiro ; Uemoto, Shinji ; Saito, Hideyuki ; Tanaka, Koichi ; Inui, Ken ichi. / Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation. In: Clinical Pharmacology and Therapeutics. 2001 ; Vol. 69, No. 5. pp. 308-316.
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abstract = "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 (MDRI), 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 MDR1 and CYP3A4 in mucosal 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 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.",
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T1 - Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation

AU - Hashida, Tohru

AU - Masuda, Satohiro

AU - Uemoto, Shinji

AU - Saito, Hideyuki

AU - Tanaka, Koichi

AU - Inui, Ken ichi

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N2 - 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 (MDRI), 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 MDR1 and CYP3A4 in mucosal 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 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.

AB - 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 (MDRI), 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 MDR1 and CYP3A4 in mucosal 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 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.

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