Impact of CYP3A7, CYP2D6 and ABCC2/ABCC3 polymorphisms on tacrolimus steady state concentrations in Bulgarian kidney transplant recipients

AbstractPolymorphisms in the genes of drug-metabolizing enzymes have the potential to contribute to inter-individual differences in drug pharmacokinetics and toxicity. A custom next-generation sequencing (NGS) panel was used in 71 kidney transplanted patients to study the polymorphisms of 11 genes relevant to the metabolism of immunosuppressive drugs. Cyclosporine A and tacrolimus concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. More than 1000 polymorphisms were found in the studied 11 genes, and 45% of them were different non-synonymous variants. Eleven missense mutations were observed in the CYP3A7 gene, resulting in increased metabolism of tacrolimus at day 21 post-transplantation (6.7 µg/L vs. 10.3 µg/L; p = 0.048). Two alleles encoding a cytochrome P450 2D6 enzyme with impaired function—CYP2D6*4 (non-functional) and CYP2D6*10 (decreased function), were found in the studied group and both of them were associated with higher levels of tacrolimus at day 14 (10.1 µg/L; p = 0.021 and 9.7 µg/L; p = 0.036, vs. 7.7 µg/L respectively). Altered function of ABC transporters C3 and C2 was also associated with increased TAC concentration. ABCC3 significantly influenced TAC metabolism by itself, but polymorphisms affecting both ABCC3 and ABCC2 resulted in higher changes: 13.6 µg/L vs. 7.9 µg/L, day 14 (p = 0.003) and 20 µg/L versus 9.3 µg/L, day 21 (p = 0.019). All associations were also checked for variants affecting the activity of CYP3A4 and CYP3A5. Despite its small size, the study points out that the pharmacogenetics of calcineurin inhibitors may also be influenced by other genes besides CYP3A4 and CYP3A5