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Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Interleukin 18 (IL-18) is a potent proinflammatory cytokine thought to down-regulate cytochrome P450 (CYP) enzyme activities. This study aimed to assess the potential influence of two functional single nucleotide polymorphisms (SNPs) in the IL-18 promoter region on the tacrolimus pharmacokinetics in Chinese renal transplant patients.

Methods

We enrolled 96 renal allograft recipients receiving tacrolimus-based immunosuppressive regiments. Two functional SNPs in the IL-18 gene promoter region at the positions –137G/C (rs187283) and –607A/C (rs1946518) and one SNP (rs776746) of CYP3A5 were genotyped using a Mass ARRAY platform. Tacrolimus daily doses (mg/day) and trough tacrolimus concentration (ng/ml) were continuously recorded for 1 month after transplantation.

Results

The tacrolimus C/D ratio was significantly associated with the IL-18 rs1946518 gene polymorphism in the first month after transplantation (P = 0.0225). We studied the influence of its polymorphism on tacrolimus C/D ratios in subjects with different CYP3A5 genotype backgrounds, and among patients with CYP3A5 expressers, the difference among the three genotypes was even more striking (P < 0.001). We did not find significant differences in tacrolimus C/D ratios between the IL-18 rs187238 genotypes, either nominally or according to the CYP3A5 genotype. In a simple linear regression model, age, hemoglobin (Hb), CYP3A5 gene polymorphisms, and IL-18 A-607C gene polymorphisms were associated with log-transformed tacrolimus C/D ratios (P < 0.05). In the final multiple linear regression model, CYP3A5 polymorphisms were the most important variant, accounting for 19.5 % of total variation involved in tacrolimus pharmacokinetics.

Conclusion

Our findings suggest that a combined analysis of CYP3A5 and IL-18 promoter polymorphisms may help clinicians develop individualized tacrolimus treatment, which is based on determining CYP3A5 genotype.

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Abbreviations

CYP3A5:

cytochrome P450, family 3, subfamily A, polypeptide 5

IL-18:

interleukin-18

SNP:

single nucleotide polymorphisms

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Acknowledgments

This work was supported by the developing Project of Science and Technology Commission of Shandong Province (2012G0021825), the 863 Program (2012AA021002), and the National Natural Science Foundation of China (Grant Number 81202609).

Declaration of interest

The authors declare no conflicts of interest and claim responsibility for the content and writing of this paper.

Author information

Authors and Affiliations

  1. Department of Urology Surgery, Shandong Qianfoshan Hospital, School of Medicine, Taishan Medical College, Shandong, China

    Jiazhen Xing

  2. Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Xiaoqing Zhang

  3. Department of Hepatobiliary Pancreatic Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Junwei Fan

  4. Department of Urology Surgery, Shandong Qianfoshan Hospital, School of Medicine, Shandong University, Shandong, China

    Bin Shen, Tongyi Men & Jianning Wang

  5. No.16766, Jingshi Road, Jinan City, China

    Tongyi Men & Jianning Wang

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  1. Jiazhen Xing
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  4. Bin Shen
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Correspondence to Tongyi Men or Jianning Wang.

Additional information

J. Xing, X. Zhang, and J. Fan are co-first authors with the same contribution to the paper.

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Xing, J., Zhang, X., Fan, J. et al. Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients. Eur J Clin Pharmacol 71, 191–198 (2015). https://doi.org/10.1007/s00228-014-1785-8

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  • DOI: https://doi.org/10.1007/s00228-014-1785-8

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