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The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients
Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therap...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062093/ https://www.ncbi.nlm.nih.gov/pubmed/33886687 http://dx.doi.org/10.1371/journal.pone.0250597 |
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author | Furuse, Maizumi Hosomi, Shuhei Nishida, Yu Itani, Shigehiro Nadatani, Yuji Fukunaga, Shusei Otani, Koji Tanaka, Fumio Nagami, Yasuaki Taira, Koichi Kamata, Noriko Watanabe, Toshio Watanabe, Kenji Fujiwara, Yasuhiro |
author_facet | Furuse, Maizumi Hosomi, Shuhei Nishida, Yu Itani, Shigehiro Nadatani, Yuji Fukunaga, Shusei Otani, Koji Tanaka, Fumio Nagami, Yasuaki Taira, Koichi Kamata, Noriko Watanabe, Toshio Watanabe, Kenji Fujiwara, Yasuhiro |
author_sort | Furuse, Maizumi |
collection | PubMed |
description | Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac. |
format | Online Article Text |
id | pubmed-8062093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-80620932021-05-04 The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients Furuse, Maizumi Hosomi, Shuhei Nishida, Yu Itani, Shigehiro Nadatani, Yuji Fukunaga, Shusei Otani, Koji Tanaka, Fumio Nagami, Yasuaki Taira, Koichi Kamata, Noriko Watanabe, Toshio Watanabe, Kenji Fujiwara, Yasuhiro PLoS One Research Article Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac. Public Library of Science 2021-04-22 /pmc/articles/PMC8062093/ /pubmed/33886687 http://dx.doi.org/10.1371/journal.pone.0250597 Text en © 2021 Furuse et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Furuse, Maizumi Hosomi, Shuhei Nishida, Yu Itani, Shigehiro Nadatani, Yuji Fukunaga, Shusei Otani, Koji Tanaka, Fumio Nagami, Yasuaki Taira, Koichi Kamata, Noriko Watanabe, Toshio Watanabe, Kenji Fujiwara, Yasuhiro The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title | The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title_full | The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title_fullStr | The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title_full_unstemmed | The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title_short | The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
title_sort | impact of cytochrome p450 3a genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062093/ https://www.ncbi.nlm.nih.gov/pubmed/33886687 http://dx.doi.org/10.1371/journal.pone.0250597 |
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