Impact of Pharmacogenetic Determinants of Tacrolimus and Mycophenolate on Adverse Events in Renal Transplant Patients

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Author(s): Kalluri Thishya, Boddupally Sreenu, Shree Bhushan Raju, Vijay Kutala*

Journal Name: Current Drug Metabolism

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Background: Graft acceptance against immunity is one of themajor challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome; however it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events.

Objective: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients.

Methods: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3, ABCB1 1236 T>C, ABCB1 2677 G>A/T, ABCB1 3435 T>C) and mycophenolate (UGT1A8*3, UGT1A9, IMPDH I, IMPDH II c.787C>T , ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing.

Results: Acute rejection (AR) was observed in 5.88% of the transplant recipients, whereas, acute tubular necrosis (ATNs) was observed in 7.45% of the patients, within early stage of the maintenance phase. Infections, such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T, c.3972C>T polymorphisms and ABCB1 3435 C-allele, were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk, and ABCC 3972C>T, CC-genotype showed protection against adverse events.

Conclusion: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.

Keywords: Tacrolimus, mycophenolate, renal transplant, acute rejection, adverse events, CYP3A5, ABCB1, UGT1A9, IMPDH.

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(E-pub Ahead of Print)
DOI: 10.2174/1389200222666210114123349
Price: $95

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