A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform

• Published in: The pharmacogenomics journal Vol. 17; no. 2; pp. 174 - 179
• Main Authors: Choi, Y, Jiang, F, An, H, Park, H J, Choi, J H, Lee, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; Nature Publishing Group
• Subjects: 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
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2015.99

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.