Influence of IL-18 and IL-10 Polymorphisms on Tacrolimus Elimination in Chinese Lung Transplant Patients

Abstract

Aims. The influence of interleukin-10 (IL-10) and interleukin-18 (IL-18) polymorphisms on tacrolimus pharmacokinetics had been described in liver and kidney transplantation. The expression of cytokines varied in different kinds of transplantation. The influence of IL-10 and IL-18 genetic polymorphisms on the pharmacokinetic parameters of tacrolimus remains unclear in lung transplantation. Methods. 51 lung transplant patients at Shanghai Pulmonary Hospital were included. IL-18 polymorphisms (rs5744247 and rs1946518), IL-10 polymorphisms (rs1800896, rs1800872, and rs3021097), and CYP3A5 rs776746 were genotyped. Dose-adjusted trough blood concentrations (C/D ratio, mg/kg body weight) in lung transplant patients during the first 4 postoperative weeks were calculated. Results. IL-18 rs5744247 allele C and rs1946518 allele A were associated with fast tacrolimus metabolism. Combined analysis showed that the numbers of low IL-18 mRNA expression alleles had positive correlation with tacrolimus C/D ratios in lung transplant recipients. The influence of IL-18 polymorphisms on tacrolimus C/D ratios was observed in CYP3A5 expresser recipients, but not in CYP3A5 nonexpresser recipients. No clinical significance of tacrolimus C/D ratios difference of IL-10 polymorphisms was found in our data. Conclusions. IL-18 polymorphisms may influence tacrolimus elimination in lung transplantation patients.

The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

“…The frequency of CYP3A5*3 variant differs among world populations, which is estimated to be 94, 68-71 and 18% in Europeans, Asians, and Africans, respectively [6]. The mutation rate in this study was 73%, comparable to previous studies in Chinese transplant recipients [16,18].…”

“…In LTx, similar results have been reported in Caucasians [12][13][14]. But studies in Chinese population are limited till now [15,16], and Chinese has a different mutation rates of CYP3A5*3 from Caucasians [6], so, there is a major void in this research area.…”

“…In Caucasians, Miano et al reported patients bearing CYP3A5*3/*3 genotype exhibited approximately 50% higher C/D than CYP3A5*1 carriers in the rst 2 weeks after LTx [13] and Zheng et al investigated later time points, from 1 month to 12 months, and also observed higher C/D in CYP3A5*3/*3 [4]. Only 1 study conducted in Chinese with a relatively small sample size of 51 recipients reported the C/D for CYP3A5*3/*3 genotype was 1.9-2.5 times higher than CYP3A5*1 carriers in the rst month [16]. In our study, the C/D for CYP3A5*3/*3 vs. CYP3A5*1 carriers were 2.88, 2.21, 2.38 and 2.18 during week 1-4, respectively, similar to the results from both Caucasian and Chinese population.…”

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

“…One prominent example relates to the rs1946518 (-607C/A) variant within the promoter of IL-18 and its effects on the metabolism of the immunosuppressive tacrolimus. Xing et al and Zhang et al demonstrated that Han-Chinese patients carrying the AA genotype (19–29% of the patients) exhibited lower concentration/dose (C/D) ratios of tacrolimus within the first month after lung or kidney transplantation than patients with an AC or CC genotype [ 87 , 88 ]. Interestingly, this relationship for the rs1946518 variant was exclusively shown for patients expressing CYP3A5*1 and functionally linked to lower expression of IL-18 mRNA in the liver.…”

The impact of cytochrome P450 3A5 genotype on early tacrolimus metabolism and clinical outcomes in lung transplant recipients

“…Except for a different frequency of CYP3A5*3 allele from Caucasians, males and older recipients seems to account for the majority of Chinese LTx population [10,11]. Till now, studies in this population are limited and usually conducted in small sample sizes, leaving a major void in this area [12,13].…”