PXR（8055C>T）多态性对健康中国受试者体内哌喹药代动力学特征无影响。
No Effect of PXR (8055C>T) Polymorphism on the Pharmacokinetic Profiles of Piperaquine in Healthy Chinese Subjects.
机构信息
School of Pharmaceutical Sciences, Shandong University, Jinan, China.
出版信息
Curr Drug Metab. 2022;23(2):164-170. doi: 10.2174/1389200223666220215151945.
BACKGROUND
Significant inter-subject variability in pharmacokinetics and clinical outcomes has been observed for the antimalarial agent piperaquine (PQ). PQ is metabolized by CYP3A4, mainly regulated by the pregnane X receptor (PXR). CYP3A4(*1B) polymorphism did not affect PQ clearance.
OBJECTIVES
The effect of PXR (8055C>T) polymorphism on the pharmacokinetic profiles of PQ was investigated.
METHODS
The pharmacokinetic profiles of PQ and its major metabolite PQ N-oxide (PQM) were studied in healthy Chinese subjects after recommended oral doses of artemisinin-PQ. Twelve subjects were genotyped using PCRRFLP (six in each group with PXR 8055CC and 8055TT), and plasma concentrations were determined by a validated LC/MS/MS method. The dose-adjusted exposure (AUC and C) to PQ or PQM was investigated, and the metabolic capability of PQ N-oxidation was determined by AUC/AUC. The antimalarial outcome of PQ was evaluated using its day 7 concentration.
RESULTS
PQM formation was mediated by CYP3A4/3A5. Interindividual variability in dose-adjusted AUC of PQ and PQM was relatively low (%CV, <30.0%), whereas a larger inter-variability was observed for C values (%CV, 68.1% for PQ). No polymorphic effect was found for PXR (C8055T) on the pharmacokinetic profiles of PQ or its Cday 7 concentrations.
CONCLUSION
Both CYP3A4 and CYP3A5 were involved in PQ clearance. The genotypes of PXR (C8055T) may not contribute to the variability in PQ pharmacokinetics as well as antimalarial outcomes. There might be a low risk of variable exposures to PQ in malaria patients carrying mutated PXR (8055C>T) genes, which deserves further study, especially in a larger sample size.
背景
抗疟药哌喹（PQ）在药代动力学和临床结果方面存在显著的个体间变异性。PQ 主要由细胞色素 P4503A4（CYP3A4）代谢，主要受孕烷 X 受体（PXR）调控。CYP3A4*1B 多态性不影响 PQ 清除率。
目的
研究 PXR（8055C>T）多态性对 PQ 药代动力学特征的影响。
方法
在健康中国受试者中，在推荐剂量的青蒿素-PQ 口服后，研究了 PQ 和其主要代谢物 PQ N-氧化物（PQM）的药代动力学特征。使用 PCRRFLP（每组 6 名，PXR 8055CC 和 8055TT）对 12 名受试者进行基因分型，并使用经过验证的 LC/MS/MS 方法测定血浆浓度。研究了 PQ 或 PQM 的剂量调整后的暴露（AUC 和 C），并通过 AUC/AUC 来确定 PQ N-氧化的代谢能力。通过 PQ 的第 7 天浓度评估 PQ 的抗疟效果。
结果
PQM 的形成由 CYP3A4/3A5 介导。PQ 和 PQM 的剂量调整 AUC 的个体间变异性相对较低（%CV，<30.0%），而 C 值的变异性较大（%CV，PQ 为 68.1%）。PXR（C8055T）多态性对 PQ 的药代动力学特征或其 Cday7 浓度无多态性影响。
结论
CYP3A4 和 CYP3A5 均参与 PQ 的清除。PXR（C8055T）的基因型可能不会导致 PQ 药代动力学和抗疟效果的变异性。在携带突变 PXR（8055C>T）基因的疟疾患者中，PQ 暴露可能存在可变性的风险较低，但需要进一步研究，特别是在更大的样本量中。
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