Abstract
Aim: Determine the effect of the genetic variants beyond CYP3A5∗3 on tacrolimus disposition. Patients & methods: We studied genetic correlates of tacrolimus trough concentrations with POR∗28, CYP3A4∗22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). Results: Subjects carrying one or more CYP3A5∗1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10-75). The presence of one or two POR∗28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5∗1 and clinical factors (p = 0.037). In subset analyses, POR∗28 was significant only in CYP3A5∗3/∗3 carriers (p = 0.03). The CYP3A4∗22 variant and the ABBC2 haplotypes were not associated. Conclusion: This study confirmed that CYP3A5∗1 was associated with lower tacrolimus trough concentrations. POR∗28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4∗22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 201.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 841-854 |
| Number of pages | 14 |
| Journal | Pharmacogenomics |
| Volume | 16 |
| Issue number | 8 |
| DOIs | |
| State | Published - Jul 1 2015 |
| Externally published | Yes |
Keywords
- ABCC2
- calcineurin inhibitor
- cytochrome P450 3A4 and 3A5
- kidney transplant
- pharmacogenomics
- pharmacokinetics
- POR
- tacrolimus
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Pharmacology