Cargando…
Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients
BACKGROUND: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant inter-subject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bentham Science Publishers
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857112/ https://www.ncbi.nlm.nih.gov/pubmed/31267867 http://dx.doi.org/10.2174/1389200220666190701094756 |
_version_ | 1783470699061444608 |
---|---|
author | Wang, Zhiqi Zhang, Nan Chen, Chaoyang Chen, Shuqing Xu, Junyu Zhou, Ying Zhao, Xia Cui, Yimin |
author_facet | Wang, Zhiqi Zhang, Nan Chen, Chaoyang Chen, Shuqing Xu, Junyu Zhou, Ying Zhao, Xia Cui, Yimin |
author_sort | Wang, Zhiqi |
collection | PubMed |
description | BACKGROUND: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant inter-subject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. OBJECTIVE: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. METHODS: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. RESULTS: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L•h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h-1)=1.69. CONCLUSION: In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study. |
format | Online Article Text |
id | pubmed-6857112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-68571122019-12-06 Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients Wang, Zhiqi Zhang, Nan Chen, Chaoyang Chen, Shuqing Xu, Junyu Zhou, Ying Zhao, Xia Cui, Yimin Curr Drug Metab Article BACKGROUND: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant inter-subject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. OBJECTIVE: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. METHODS: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. RESULTS: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L•h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h-1)=1.69. CONCLUSION: In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study. Bentham Science Publishers 2019-06 2019-06 /pmc/articles/PMC6857112/ /pubmed/31267867 http://dx.doi.org/10.2174/1389200220666190701094756 Text en © 2019 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/legalcode This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. |
spellingShingle | Article Wang, Zhiqi Zhang, Nan Chen, Chaoyang Chen, Shuqing Xu, Junyu Zhou, Ying Zhao, Xia Cui, Yimin Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title | Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title_full | Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title_fullStr | Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title_full_unstemmed | Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title_short | Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients |
title_sort | influence of the oatp polymorphism on the population pharmacokinetics of methotrexate in chinese patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857112/ https://www.ncbi.nlm.nih.gov/pubmed/31267867 http://dx.doi.org/10.2174/1389200220666190701094756 |
work_keys_str_mv | AT wangzhiqi influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT zhangnan influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT chenchaoyang influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT chenshuqing influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT xujunyu influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT zhouying influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT zhaoxia influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients AT cuiyimin influenceoftheoatppolymorphismonthepopulationpharmacokineticsofmethotrexateinchinesepatients |