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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...

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Autores principales: Wang, Zhiqi, Zhang, Nan, Chen, Chaoyang, Chen, Shuqing, Xu, Junyu, Zhou, Ying, Zhao, Xia, Cui, Yimin
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
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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.
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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
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