Influence of cytochrome p450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mrna expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients

Miwa Uesugi, Mio Hosokawa, Haruka Shinke, Emina Hashimoto, Tamotsu Takahashi, Tomoki Kawai, Kazuo Matsubara, Kohei Ogawa, Yasuhiro Fujimoto, Shinya Okamoto, Toshimi Kaido, Shinji Uemoto, Satohiro Masuda

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

Original languageEnglish
Pages (from-to)1814-1821
Number of pages8
JournalBiological and Pharmaceutical Bulletin
Volume36
Issue number11
DOIs
Publication statusPublished - Nov 1 2013

Fingerprint

Cytochrome P-450 CYP3A
Living Donors
Tacrolimus
Pharmacokinetics
Transplants
Liver
Intestines
Genotype
Alleles
Incidence
Graft Rejection

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Influence of cytochrome p450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mrna expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients. / Uesugi, Miwa; Hosokawa, Mio; Shinke, Haruka; Hashimoto, Emina; Takahashi, Tamotsu; Kawai, Tomoki; Matsubara, Kazuo; Ogawa, Kohei; Fujimoto, Yasuhiro; Okamoto, Shinya; Kaido, Toshimi; Uemoto, Shinji; Masuda, Satohiro.

In: Biological and Pharmaceutical Bulletin, Vol. 36, No. 11, 01.11.2013, p. 1814-1821.

Research output: Contribution to journalArticle

Uesugi, Miwa ; Hosokawa, Mio ; Shinke, Haruka ; Hashimoto, Emina ; Takahashi, Tamotsu ; Kawai, Tomoki ; Matsubara, Kazuo ; Ogawa, Kohei ; Fujimoto, Yasuhiro ; Okamoto, Shinya ; Kaido, Toshimi ; Uemoto, Shinji ; Masuda, Satohiro. / Influence of cytochrome p450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mrna expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients. In: Biological and Pharmaceutical Bulletin. 2013 ; Vol. 36, No. 11. pp. 1814-1821.
@article{79f88209797a4404ba11800ff9f0ca85,
title = "Influence of cytochrome p450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mrna expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients",
abstract = "Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7{\%} vs. 14.6{\%}, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9{\%} in CYP3A4*1/*1 vs. 12.5{\%} in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.",
author = "Miwa Uesugi and Mio Hosokawa and Haruka Shinke and Emina Hashimoto and Tamotsu Takahashi and Tomoki Kawai and Kazuo Matsubara and Kohei Ogawa and Yasuhiro Fujimoto and Shinya Okamoto and Toshimi Kaido and Shinji Uemoto and Satohiro Masuda",
year = "2013",
month = "11",
day = "1",
doi = "10.1248/bpb.b13-00509",
language = "English",
volume = "36",
pages = "1814--1821",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "11",

}

TY - JOUR

T1 - Influence of cytochrome p450 (CYP) 3A4*1G polymorphism on the pharmacokinetics of tacrolimus, probability of acute cellular rejection, and mrna expression level of CYP3A5 rather than CYP3A4 in living-donor liver transplant patients

AU - Uesugi, Miwa

AU - Hosokawa, Mio

AU - Shinke, Haruka

AU - Hashimoto, Emina

AU - Takahashi, Tamotsu

AU - Kawai, Tomoki

AU - Matsubara, Kazuo

AU - Ogawa, Kohei

AU - Fujimoto, Yasuhiro

AU - Okamoto, Shinya

AU - Kaido, Toshimi

AU - Uemoto, Shinji

AU - Masuda, Satohiro

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

AB - Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n=412) and/or recipients (n=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p=0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p=0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

UR - http://www.scopus.com/inward/record.url?scp=84888595114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888595114&partnerID=8YFLogxK

U2 - 10.1248/bpb.b13-00509

DO - 10.1248/bpb.b13-00509

M3 - Article

C2 - 24189425

AN - SCOPUS:84888595114

VL - 36

SP - 1814

EP - 1821

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 11

ER -