Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients

Miwa Uesugi, Satohiro Masuda, Toshiya Katsura, Fumitaka Oike, Yasutsugu Takada, Ken Ichi Inui

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CVP345*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/ dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.

Original languageEnglish
Pages (from-to)119-127
Number of pages9
JournalPharmacogenetics and Genomics
Volume16
Issue number2
DOIs
Publication statusPublished - Feb 2006

Fingerprint

Cytochrome P-450 CYP3A
Living Donors
Tacrolimus
Liver
Genotype
Liver Transplantation
Transplant Recipients
Transplants
Intestines
Pharmacokinetics
Tissue Donors
P-Glycoprotein
Gene Frequency

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. / Uesugi, Miwa; Masuda, Satohiro; Katsura, Toshiya; Oike, Fumitaka; Takada, Yasutsugu; Inui, Ken Ichi.

In: Pharmacogenetics and Genomics, Vol. 16, No. 2, 02.2006, p. 119-127.

Research output: Contribution to journalArticle

Uesugi, Miwa ; Masuda, Satohiro ; Katsura, Toshiya ; Oike, Fumitaka ; Takada, Yasutsugu ; Inui, Ken Ichi. / Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 2. pp. 119-127.
@article{defa1011b29346859786bb8f3611a8c5,
title = "Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients",
abstract = "It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CVP345*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80{\%} in recipients and 77{\%} in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/ dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.",
author = "Miwa Uesugi and Satohiro Masuda and Toshiya Katsura and Fumitaka Oike and Yasutsugu Takada and Inui, {Ken Ichi}",
year = "2006",
month = "2",
doi = "10.1097/01.fpc.0000184953.31324.e4",
language = "English",
volume = "16",
pages = "119--127",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients

AU - Uesugi, Miwa

AU - Masuda, Satohiro

AU - Katsura, Toshiya

AU - Oike, Fumitaka

AU - Takada, Yasutsugu

AU - Inui, Ken Ichi

PY - 2006/2

Y1 - 2006/2

N2 - It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CVP345*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/ dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.

AB - It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CVP345*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/ dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.

UR - http://www.scopus.com/inward/record.url?scp=31344466713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=31344466713&partnerID=8YFLogxK

U2 - 10.1097/01.fpc.0000184953.31324.e4

DO - 10.1097/01.fpc.0000184953.31324.e4

M3 - Article

C2 - 16424824

AN - SCOPUS:31344466713

VL - 16

SP - 119

EP - 127

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 2

ER -