Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients

Zuo, Xiaoxia; Ng, Chee M.; Barrett, Jeffrey S.; Luo, Aijing; Zhang, Bikui; Deng, Chen-hui; Xi, Lan-yan; Cheng, Ke; Ming, Yingzi; Yang, Guangzheng; Pei, Qi; Zhu, Lan; Yuan, Hong; Liao, Hai-qiang; Ding, Junjie; Wu, Di; Zhou, Yanan; Ningning, Jing; Huang, Zhijun

doi:10.1097/fpc.0b013e32835fcbb6

Cited by 115 publications

(144 citation statements)

References 23 publications

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“…No influence on the TAC logC0/D was observed for rs4646437 at different time points in CYP3A5 expressers. This is consistent with another study of CYP3A4 rs2242480 [41] . Actually, CYP3A4 rs2242480 is a functional SNP that could increase the activity of CYP3A4, and it resembles rs4646437 that can affect the hepatic CYP3A4 protein expression [19,42] .…”

Section: Discussionsupporting

confidence: 82%

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P=0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P=0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

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Section: Discussionsupporting

confidence: 82%

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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“…Such results have been reported previously in the literature concerning this polymorphism. [5][6][7][8][9][10] A previous study by Patel and associates studied the effect of CYP3A5 polymorphism on tacrolimus drug dosing in North Indian renal allograft recipients. 11 To our knowledge, the present study is the first study to show the association between CYP3A5 genetic polymorphism and tacrolimus drug level in a South Indian population.…”

Section: Discussionmentioning

confidence: 99%

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2015

Exp Clin Transplant

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Objectives: Tacrolimus is the cornerstone for immunosuppression in renal transplant and is metabolized by the cytochrome P 450 3A (CYP3A) subfamily of enzymes in the liver and small intestine. A polymorphism in intron 3 of the CYP3A5 gene affects the expression of this enzyme and tacrolimus trough blood levels. The purpose of this study was to identify the proportion of CYP3A5 gene polymorphisms in South Indian renal transplant patients and determine the effect of CYP3A5 gene polymorphisms on tacrolimus trough blood levels in patients with and without CYP3A5 expression. Materials and Methods:We included 25 adult patients who underwent renal transplant at Government Medical College, Trivandrum. All patients received tacrolimus (dose, 0.1 mg/kg/body weight, in 2 divided doses). Tacrolimus trough blood levels were determined on postoperative day 6. The CYP3A5 genotype analysis was performed by polymerase chain reaction amplification of target and detection by restriction fragment length polymorphism analysis. Results: The CYP3A5*1/*1 genotype was detected in 5 recipients (20%), *1/*3 genotype in 5 recipients (20%), and *3/*3 genotypes in 15 recipients (60%) of the total 25 graft recipients.Mean tacrolimus level in the CYP3A5*1/*1 group was 5.154 ng/mL (range, 4.42 to 6.5 ng/mL), CYP3A5*1/*3 group was 5.348 ng/mL (range, 3.1 to 9.87 ng/mL), and CYP3A5*3/*3 group was 9.483 ng/mL (range, 4.5 to14.1 ng/mL). Acute rejection episodes were significantly more frequent for CYP3A5*1/*1 homozygous patients (40%) than patients with CYP3A5*1/*3 (20%) or CYP3A5*3/*3 (13%) genotypes. Conclusions: Most patients carried the mutant allele CYP3A5*3 (A6986G). Tacrolimus drug level correlated well with presence or absence of CYP3A5 polymorphisms. Acute rejection episodes were more frequent in expressors, and they may require higher doses of tacrolimus. Similarly, tacrolimus nephrotoxicity was more frequent in nonexpressors. Therefore, CYP3A5 polymorphism analysis before renal transplant may help determine the optimal dose of tacrolimus in this population and prevent acute rejection episodes or tacrolimus toxicity.

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“…Research in cases of renal, lung, and heart transplantation has confirmed that there is a strong correlation between cytochrome P450 (CYP) 3A5 gene polymorphism and patient-specific differences in responses to tacrolimus (Zheng et al, 2003(Zheng et al, , 2004Macphee et al, 2005;Li et al, 2007;Zuo et al, 2013). However, the situation is more complex in cases of liver transplantation.…”

Section: Introductionmentioning

confidence: 96%

Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We evaluated the clinical efficacy of tailoring tacrolimus dosage to cytochrome P450 (CYP) 3A5 genotype in liver transplant patients. One hundred patients who received tacrolimus-based therapy were included in the retrospective study in which the relationship between the tacrolimus blood trough concentration/dosage ratio and the CYP3A5 genotype of both donors and recipients was determined. Subsequently, 106 patients were continuously enrolled in a prospective study and followedup for 6 months; the relationship between tacrolimus dosage and CYP3A5 genotype was also determined. Rates of acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, and hyperglycemia were compared between the groups. During the 6 months following liver transplantation, the mean tacrolimus concentration/dosage ratio among patients who did not have the CYP3A5*1 genotype and who received a transplant from a L. Wang et al. 3192©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 3191-3199 (2015) donor with the same genotype (24/100, 24% of patients) was higher than that among patients who did have the CYP3A5*1 genotype and/or had a donor with the same genotype (76/100, 76% of patients). In the second part of the study, the tacrolimus dosage was tailored to CYP3A5 genotype and 24 patients (22.64%) received a lower dose. There was an obvious decrease in acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, hyperglycemia, and Pneumocystis carinii infection among the latter group. A lower tacrolimus dose was suitable for about 25% of the liver transplant patients, as these patients did not have the CYP3A5*1 genotype and received a transplant from a donor with the same genotype. Tailoring the tacrolimus dosage according to the CYP3A5 genotype could reduce rejection and adverse effects.

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Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients

Cited by 115 publications

References 23 publications

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

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Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

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