Russo J, Russo M E, Smith R A, Pershing L K
J Clin Pharmacol. 1982 May-Jun;22(5-6):264-70. doi: 10.1002/j.1552-4604.1982.tb02672.x.
Two different chronic dosing regimens of quinidine gluconate were administered to each of four healthy volunteers in a pilot study to evaluate quinidine for nonlinear pharmacokinetics. Analysis of plasma quinidine levels following the last dose indicates that disproportionate increases in steady-state plasma concentrations can occur in some subjects as the daily dose increases. Measurement of 2'-oxoquinidinone (2'-OXO) and 3-hydroxyquinidine (3-OH) metabolites revealed that the formation of 2'-OXO is proportional to the availability of quinidine base. Hydroxylation was a more variable process. Rate-limited hydroxylation was documented in one subject, and an apparent increase in hepatic microsomal enzyme-mediated hydroxylation was shown in a second subject who ingested large amounts of caffeine daily. By using a highly selective high-performance liquid chromatography assay technique, the total body clearance of quinidine was found to be greater than previously published data. Our results suggest that some individuals may exhibit dose-dependent elimination of quinidine and that the variability in quinidine's pharmacokinetics is related in part to its hydroxylation. Future studies must use highly specific quinidine assays and control for variables that may influence this route of metabolism.
在一项初步研究中，对四名健康志愿者分别给予两种不同的葡萄糖酸奎尼丁慢性给药方案，以评估奎尼丁的非线性药代动力学。对最后一剂后的血浆奎尼丁水平分析表明，随着日剂量增加，一些受试者的稳态血浆浓度可能会出现不成比例的增加。对2'-氧代奎尼丁（2'-OXO）和3-羟基奎尼丁（3-OH）代谢物的测量显示，2'-OXO的形成与奎尼丁碱的可用性成正比。羟基化是一个更具变异性的过程。在一名受试者中记录到了限速羟基化，而在另一名每天摄入大量咖啡因的受试者中，肝微粒体酶介导的羟基化明显增加。通过使用一种高度选择性的高效液相色谱分析技术，发现奎尼丁的全身清除率高于先前公布的数据。我们的结果表明，一些个体可能表现出奎尼丁的剂量依赖性消除，并且奎尼丁药代动力学的变异性部分与其羟基化有关。未来的研究必须使用高度特异性的奎尼丁分析方法，并控制可能影响这种代谢途径的变量。
