Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
Ther Drug Monit. 2010 Jun;32(3):346-52. doi: 10.1097/FTD.0b013e3181da79d6.
Quinine is one of the most effective antimalarial drugs, although its clinical use is limited as a result of its narrow safety margin. Quinine is a substrate of the polymorphic p-glycoprotein and CYP3A4/3A5. This study aimed to examine the effects of genetic variations in ABCB1 and CYP3A5 genes, sex, demographic, and biochemical variables (serum albumin, creatinine, alanine aminotransferase and albumin) on quinine disposition among Ugandans. Quinine (600 mg) was orally administered to 140 healthy volunteers. Quinine and its metabolite 3-hydroxyquinine concentrations were determined from 16-hour postdose plasma by high-performance liquid chromatography. CYP3A5 activity was measured using quinine/3-hydroxyquinine ratio (metabolic ratio). Genotyping for a total of 20 single nucleotide polymorphisms in ABCB1 (n = 13) and CYP3A5 (n = 7) was done using Taqman and minisequencing on microarray. There were 20.5- and 13-fold variations in body weight-adjusted plasma quinine concentrations (mean +/- standard deviation, 5.26 +/- 2.5 mumol/L; range, 0.88-18.10 mumol/L) and quinine-to-3-hydroxyquinine metabolic ratio (mean +/- standard deviation, 7.68 +/- 3.3 mumol/L; range, 1.66-22.3 mumol/L), respectively. Weight-adjusted plasma quinine concentration was significantly influenced by sex and ABCB1 haplotype. There was a significant sex difference in quinine metabolic ratio, women being faster metabolizers than men (P = 0.01). CYP3A5 genotype/haplotype significantly (P = 0.03) influenced quinine disposition with a clear CYP3A5*1 gene dose effect. The result confirms that quinine disposition is influenced mainly by sex as well as by ABCB1 and CYP3A5 genotypes. Despite being fast metabolizers, women display higher quinine bioavailability than men in Uganda. This may have clinical significance in determining an individual's susceptibility to quinine-associated adverse reactions such as cinchonism.
奎宁是最有效的抗疟药物之一，但其临床应用受到限制，因为其安全性范围较窄。奎宁是多态性 P-糖蛋白和 CYP3A4/3A5 的底物。本研究旨在探讨 ABCB1 和 CYP3A5 基因的遗传变异、性别、人口统计学和生化变量（血清白蛋白、肌酐、丙氨酸氨基转移酶和白蛋白）对乌干达人体内奎宁处置的影响。140 名健康志愿者口服给予 600mg 奎宁。高效液相色谱法测定 16 小时后血浆中奎宁及其代谢物 3-羟基奎宁的浓度。使用奎宁/3-羟基奎宁比（代谢比）测量 CYP3A5 活性。使用 Taqman 和微阵列上的 minisequencing 对 ABCB1（n=13）和 CYP3A5（n=7）的总共 20 个单核苷酸多态性进行基因分型。体重校正后的血浆奎宁浓度（平均值±标准差，5.26±2.5μmol/L；范围，0.88-18.10μmol/L）和奎宁与 3-羟基奎宁代谢比（平均值±标准差，7.68±3.3μmol/L；范围，1.66-22.3μmol/L）分别有 20.5 倍和 13 倍的变化。体重校正后的血浆奎宁浓度受性别和 ABCB1 单倍型的显著影响。奎宁代谢比存在显著的性别差异，女性比男性更快代谢（P=0.01）。CYP3A5 基因型/单倍型对奎宁处置有显著影响（P=0.03），明显存在 CYP3A5*1 基因剂量效应。结果证实，奎宁处置主要受性别以及 ABCB1 和 CYP3A5 基因型的影响。尽管女性是快速代谢者，但在乌干达，女性的奎宁生物利用度高于男性。这在确定个体对奎宁相关不良反应（如金鸡纳反应）的易感性方面可能具有临床意义。
