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

Abstract

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.
 doi: https://doi.org/10.12669/pjms.38.7.6180
 How to cite this:Azam F, Khan M, Shaheen A, Bhatti AH. Effect of CYP3A4 and PPARA polymorphism on concentration-to-dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients. Pak J Med Sci. 2022;38(7):---------. doi: https://doi.org/10.12669/pjms.38.7.6180
 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genotype‐Guided Model for Prediction of Tacrolimus Initial Dosing After Lung Transplantation

“…Candidate single nucleotide polymorphisms (SNPs) were mainly selected from previously reported literature, which may potentially affect tacrolimus pharmacokinetics in solid‐organ transplantation. All SNPs and their respective genes analyzed in this study are listed in Table S1 5,8,16–30 . For genotyping, briefly, a 0.5‐mL blood sample was collected and genomic DNA was extracted from ethylenediaminetetraacetic acid‐anticoagulated peripheral blood samples using a commercially available DNA purification kit (EasyPure Blood Genomic DNA Kit, Transgene Biotech).…”

“…All SNPs and their respective genes analyzed in this study are listed in Table S1. 5,8,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] For genotyping, briefly, a 0.5-mL blood sample was collected and genomic DNA was extracted from ethylenediaminetetraacetic acid-anticoagulated peripheral blood samples using a commercially available DNA purification kit (EasyPure Blood Genomic DNA Kit, Transgene Biotech). All samples with a call rate greater than 95% were genotyped using an Infinium Asian Screening Array-China Health Industry Alliance Bead chip (Illumina, Inc.) according to the Illumina Infinium HTS chip standard operating procedures.…”