Kaukonen K M, Olkkola K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 1997 Nov;62(5):510-7. doi: 10.1016/S0009-9236(97)90046-1.
Quinidine is eliminated mainly by CYP3A4-mediated metabolism. Itraconazole interacts with some but not all of the substrates of CYP3A4; it is therefore important to study the possible interaction of itraconazole with quinidine.
A double-blind, randomized, two-phase crossover study design was used with nine healthy volunteers. Itraconazole (200 mg) or placebo was ingested once a day for 4 days. A single 100 mg oral dose of quinidine sulfate was ingested on day 4. Plasma concentrations of quinidine, itraconazole, and hydroxyitraconazole, as well as cumulative excretion of quinidine into urine, were determined up to 24 hours. The ECG, heart rate, and blood pressure were also recorded up to 24 hours.
On average the peak plasma concentration of quinidine increased to 1.6-fold (p < 0.05), and the area under the concentration-time curve of quinidine increased to 2.4-fold (p < 0.01) by itraconazole. The elimination half-life of quinidine was prolonged 1.6-fold (p < 0.001), and the area under the 3-hydroxyquinidine/quinidine ratio-time curve decreased to one-fifth (p < 0.001) by itraconazole. The renal clearance of quinidine decreased 50% (p < 0.001) by itraconazole, whereas the creatinine clearance was unaffected. The QTc interval correlated with the concentrations of quinidine during both itraconazole and placebo phases (r2 = 0.71 and r2 = 0.79, respectively; p < 0.01), although only minor changes between the phases were observed in other pharmacodynamic variables.
Itraconazole increases plasma concentrations of oral quinidine, probably by inhibiting the CYP3A4 isozyme during the first-pass and elimination phases of quinidine. The decreased renal clearance of quinidine might be the result of the inhibition of P-glycoprotein-mediated tubular secretion of quinidine by itraconazole. The concentrations of quinidine should be closely monitored if itraconazole or some other potent CYP3A inhibitors are used with quinidine.
奎尼丁主要通过CYP3A4介导的代谢途径消除。伊曲康唑与部分而非全部CYP3A4底物相互作用；因此，研究伊曲康唑与奎尼丁之间可能的相互作用具有重要意义。
采用双盲、随机、两阶段交叉研究设计，纳入9名健康志愿者。伊曲康唑（200mg）或安慰剂每天服用1次，共4天。在第4天口服100mg硫酸奎尼丁单次剂量。测定至24小时内奎尼丁、伊曲康唑和羟基伊曲康唑的血浆浓度，以及奎尼丁在尿液中的累积排泄量。同时记录至24小时内的心电图、心率和血压。
平均而言，伊曲康唑使奎尼丁的血浆峰浓度增加至1.6倍（p<0.05），奎尼丁浓度-时间曲线下面积增加至2.4倍（p<0.01）。伊曲康唑使奎尼丁的消除半衰期延长1.6倍（p<0.001），3-羟基奎尼丁/奎尼丁比值-时间曲线下面积降至五分之一（p<0.001）。伊曲康唑使奎尼丁的肾清除率降低50%（p<0.001），而肌酐清除率未受影响。在伊曲康唑和安慰剂阶段，QTc间期均与奎尼丁浓度相关（r2分别为0.71和0.79；p<0.01），尽管在其他药效学变量方面各阶段间仅观察到微小变化。
伊曲康唑可能通过在奎尼丁的首过和消除阶段抑制CYP3A4同工酶，从而增加口服奎尼丁的血浆浓度。奎尼丁肾清除率降低可能是伊曲康唑抑制P-糖蛋白介导的奎尼丁肾小管分泌的结果。如果伊曲康唑或其他强效CYP3A抑制剂与奎尼丁合用，应密切监测奎尼丁浓度。
