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

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™ 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. Our results agree with previous studies that CYP3A5*3 (rs776746) has a significant impact on the tacrolimus PK. The association identified for the first time between a SNP (rs3814055) in NR1I2 gene and the tacrolimus PK is interesting because NR1I2 gene encodes PXR, a transcriptional regulator of CYP3A enzymes

however, this association warrants further in-vitro and in-vivo studies. Using more than just one data analysis method may improve the interpretation of the results of gene association studies.