CYP3A5、CYP3A4和POR基因的年龄及等位基因变体对塞尔维亚儿科肾移植受者中环孢素A药代动力学的影响

Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia.

作者信息

Cvetković Mirjana, Zivković Maja, Bundalo Maja, Gojković Ivana, Spasojević-Dimitrijeva Brankica, Stanković Aleksandra, Kostić Mirjana

机构信息

*Department of Nephrology, University Children's Hospital; †Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences "VINCA," University of Belgrade; and ‡School of Medicine, University of Belgrade, Belgrade, Serbia.

出版信息

Ther Drug Monit. 2017 Dec;39(6):589-595. doi: 10.1097/FTD.0000000000000442.

DOI:10.1097/FTD.0000000000000442

PMID:29135906

Abstract

BACKGROUND

The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR28). The aim of this study was to assess the impact of age, CYP3A53, CYP3A422, and POR28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients.

METHODS

Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A53, CYP3A422, and POR*28.

RESULTS

CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 ± 12.75 versus 22.44 ± 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR1/1 genotype (165.54 ± 70.40 versus 210.55 ± 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 ± 4.72 versus 34.19 ± 11.89, P = 0.001) and C2/dose (106.75 ± 26.99 versus 209.20 ± 71.57, P < 0.001) compared with older children. Carriers of CYP3A53 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR*28 allele aged ≤6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P < 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016).

CONCLUSIONS

Younger age, POR28 allele, and CYP3A53 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.

摘要

背景

环孢素A（CsA）药代动力学的个体间差异可能由细胞色素P450 3A（CYP3A）亚家族的异质性来解释。CYP3A酶活性的改变与P450氧化还原酶基因（POR28）的变异等位基因相关。本研究的目的是评估年龄、CYP3A53、CYP3A422和POR28等位基因对小儿肾移植受者CsA药代动力学的影响。

方法

对接受CsA治疗的肾移植患者（n = 47）进行CYP3A53、CYP3A422和POR*28基因分型。

结果

与表达者相比，CYP3A5不表达者的总体剂量调整前浓度（C0/剂量；每毫克/千克纳克/毫升）更高（31.48±12.75对22.44±7.12，P = 0.01）。携带POR28等位基因的CYP3A5不表达者的总体剂量调整浓度（C2/剂量）低于携带POR1/1基因型者（165.54±70.40对210.55±79.98，P = 0.02），以年龄作为协变量。6岁及以下儿童的总体C0/剂量（18.82±4.72对34.19±11.89，P = 0.001）和C2/剂量（106.75±26.99对209.20±71.57，P < 0.001）低于年龄较大的儿童。年龄≤6岁的CYP3A53等位基因携带者在大多数时间点需要更高剂量的CsA，且C0/剂量和C2/剂量低于该等位基因的年龄较大携带者。年龄≤6岁的POR*28等位基因携带者需要更高剂量的CsA，而与该等位基因的年龄较大携带者相比，他们在大多数时间点的C0/剂量和C2/剂量更低。年龄（P < 0.002）和CYP3A5变异（P < 0.02）对总体C0/剂量有显著影响，而年龄（P < 0.00001）和POR变异（P = 0.05）对C2/剂量有显著影响。对6岁以下患者总体C2/剂量的回归总结显示，CYP3A5和POR变异均有显著影响（P < 0.016）。