<p>Effects of CYP3A5 Polymorphisms on Efficacy and Safety of Tacrolimus Therapy in Patients with Idiopathic Membranous Nephropathy</p>

Abstract

Background: Tacrolimus (TAC) is beneficial for patients with idiopathic membranous nephropathy (IMN). It has a narrow therapeutic concentration range and many factors influence TAC blood concentration. CYP3A5 is the most important enzyme in TAC metabolism. The aim of this study was to analyze the effects of CYP3A5 gene polymorphisms on the efficacy and safety of TAC in IMN patients. Patients and Methods: Patients with IMN who received oral TAC (0.05-0.075mg/kg/day) combined with prednisone (0.5mg/kg/day) from March 2016 to October 2018 were included. The data of clinical characteristics, therapeutic drugs and adverse reactions of patients were collected at baseline and during 24 weeks of treatment. Patients were divided into two groups according to different CYP3A5 genetic polymorphisms. The significant differences in the efficacy and side effects between the two groups were analyzed. Results: A total of 76 patients who completed follow-up were divided into CYP3A5 nonexpresser (CYP3A5*3/*3) group and CYP3A5 expresser (CYP3A5 *1/*3) group. The significant association between the CYP3A5 phenotype and TAC metabolism was observed. A total of 43 case-times patients exhibited adverse effects. The infection rate in CYP3A5 nonexpresser group (21.95%) was remarkably higher than the rate in CYP3A5 expresser group (5.71%). Blood concentration and C 0 /D levels were risk factors for adverse events through logistic regression analysis. There was no statistical difference between the study groups with respect to the efficacy. Conclusion: Our results demonstrated that CYP3A5 polymorphisms had important guiding roles in the treatment of IMN with tacrolimus. CYP3A5 expressers required higher daily doses of TAC to achieve the target drug concentration, but with fewer side effects. CYP3A5 genetic polymorphism might be used for TAC dosing adjustment to optimize the treatment for patients with IMN.

Exploring the Knowledge, Attitude, and Practice of Sudanese Medical Doctors Towards Tacrolimus, at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan (2022 – 2023)

“…The observations among the different Sudanese ethnic groups tacrolimus trough concentrations were found to be variable, as Arabs and Fulani were observed to have low trough concentrations (n=6; 40%), while Nuba and Beja were observed to have high trough concentrations (n=5; 33.3%), instead of fur observed to had fluctuations (n=2; 13.3%). In many studies in literature the tacrolimus trough concentrations were found to had significant correlation with the CYP3A5 genotypes and tacrolimus level, CYP3A5(*1/1)/(*1/3) known as expressor, indicated high dose required to obtained the target level, and CYP3A5 (*3/3) non-expressor therefore, low dose required for those category of patients to prevent toxicity (20,25,26). No study was done yet to detect the genotypes of the Sudanese population of kidney transplants, these results could be confirmed when the genotype alleles investigate.…”

Meta-analysis of the effects of CYP3A5*3 gene polymorphisms on tacrolimus blood concentration and effectiveness in Chinese patients with membranous nephropathy

“…Then, two studies with no available data on reported outcomes and four studies without concerning outcomes were excluded. As a result, eight studies involving 498 Chinese membranous nephropathy patients were finally included through screening (Ye et al, 2014;Yang et al, 2015;Wei et al, 2018;Lin et al, 2019a;Wu, 2019;Wang, 2020;Zhang et al, 2020;Xu et al, 2021). The course of study selection is given in Figure 1.…”

“…A total of seven studies (Yang et al, 2015;Wei et al, 2018;Lin et al, 2019a;Wu, 2019;Wang, 2020;Zhang et al, 2020;Xu et al, 2021) reported the relationship between the AA + AG genotype (referred to as expressers) and the GG genotype (referred to as non-expressers) TAC blood trough concentrations in CYP3A5*3 genotypes. As the different durations of drug administration may have an impact on the pharmacokinetics and pharmacodynamics of TAC, the studies were divided into subgroups for analysis, according to the duration of TAC administration: ≤1 month, 1-6 months, and ≥6 months.…”

“…Five studies (Yang et al, 2015;Wu, 2019;Wang, 2020;Zhang et al, 2020;Xu et al, 2021) reported the TAC C0/D between the AA + AG and GG genotypes in MN patients. The heterogeneity results showed statistical heterogeneity between the two subgroups: ≤1 month (p < 0.01, I 2 = 92.2%) and 1-6 months (p = 0.064, I 2 = 55%).…”

Interaction of tacrolimus through hedgehog signaling pathway: An in vitro evaluation using rat hepatocytes

“…However, paucity of information about the underlying molecular mechanisms in tandem with meager data is an obstacle to conclude the risks associated with adverse effects of this drug in case of prolonged course of treatment. [3][4][5][6][7] Immunosuppressive drugs may also have off target effects due to impaired mitochondrial and T-cell functions which lead to production of reactive oxygen species and induction of apoptotic cell death. 8 Patients undergoing immunosuppressive therapy after organ transplantation often display obesity and hyperlipidemia owing to accumulation of triglycerides in liver, therefore, liver targeted management should be taken into account to avoid liver complications.…”