Effect of CYP3A4 and PPARA polymorphism on concentration-to-dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients

OBJECTIVES: Polymorphism in cytochrome P450 3A4 (CYP3A4) and its regulatory gene peroxisome proliferator activated receptor (PPARA) may significantly affect the metabolism of tacrolimus. This study aims to explore the effect of the single nucleotide polymorphisms (SNP) of cytochrome P450 3A4 and PPARA on the pharmacological variables of adverse effects and the concentration-to-dose ratio (CDR) of the immune suppressant drug tacrolimus in Pakistani liver transplant recipients. METHODS: Eighty-one liver transplant patients were included and their demographic and clinical data were recorded. Dosages and trough levels of tacrolimus measured by electrochemiluminescence (ECLIA) were recorded daily. Genotyping for transplant recipients was performed for CYP3A4 rs35599367, PPARA rs4253728 and rs4823613. Incidence of sepsis, acute cellular rejection (ACR) and other adverse effects were recorded. RESULTS: Liver transplant recipients with CYP3A4 rs35599367 CT and TT genotype reported higher tacrolimus CDR compared to the CC genotype during week-1 (p<0.001) and week-2 (p =0.03) post-transplantation period. CYP3A4 rs35599367 polymorphism presented a significant association with nephrotoxicity, sepsis, seizures and psychosis. Significant association of PPARA rs4253728 and PPAARA rs4823613 polymorphism with ACR was observed. CONCLUSION: Genotyping for CYP3A4 rs35599367 polymorphism during dose titration may shorten the duration to reach optimal tacrolimus trough levels and may help predict adverse events in transplant recipients receiving tacrolimus; genotyping for PPARA rs4253728 and rs4823613 may predict the incidence of ACR.