A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform
Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMET TM Plus microarray in 42 hea...
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| Published in | The pharmacogenomics journal Vol. 17; no. 2; pp. 174 - 179 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
01.03.2017
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1470-269X 1473-1150 1473-1150 |
| DOI | 10.1038/tpj.2015.99 |
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| Abstract | Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the
CYP3A5*3
polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMET
TM
Plus microarray in 42 healthy males. Aside from
CYP3A5*3,
the rs3814055 polymorphism in the
NR1I2
gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUC
last
) was 3.42 times greater in subjects with homozygous mutations in both genes (
CYP3A5*3/*3
and
NR1I2
T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUC
last
. An
in vitro
luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant. |
|---|---|
| AbstractList | Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast ) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast . An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant. Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant.Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant. Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMET TM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUC last ) was 3.42 times greater in subjects with homozygous mutations in both genes ( CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUC last . An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant. |
| Author | Choi, Y Choi, J H An, H Park, H J Lee, H Jiang, F |
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| Snippet | Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the
CYP3A5*3
polymorphism. The... Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The... |
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| SubjectTerms | 45/41 45/61 45/77 692/308 692/700/565 Biomedical and Life Sciences Biomedicine DNA microarrays Gene Expression Gene polymorphism Genetic diversity Human Genetics Oncology original-article Pharmacogenomics Pharmacokinetics Pharmacotherapy Polymorphism Psychopharmacology Tacrolimus |
| Title | A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform |
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