Analytical Biochemistry and Mass Spectrometry Core Facility, Department of Pharmacy, University of Groningen, Groningen, The Netherlands.
Anal Chem. 2011 Jul 15;83(14):5519-25. doi: 10.1021/ac200897p. Epub 2011 Jun 27.
Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of lidocaine, a test drug compound, on a platinum electrode. Lidocaine was oxidized at constant potential and by square-wave potential pulses with different cycle times, and the reaction products were analyzed by liquid chromatography-mass spectrometry [LC-MS(/MS)]. Application of constant potentials of up to +5.0 V resulted in relatively low yields of N-dealkylation and 4-hydroxylation products, while oxidation by square-wave potential pulses generated up to 50 times more of the 4-hydroxylation product at cycle times between 0.2 and 12 s (estimated yield of 10%). The highest yield of the N-dealkylation product was obtained at cycle times shorter than 0.2 s. Tuning of the cycle time is thus an important parameter to modulate the selectivity of electrochemical oxidation reactions. The N-oxidation product was only obtained by electrochemical oxidation under air atmosphere due to reaction with electrogenerated hydrogen peroxide. Square-wave potential pulses may also be applicable to modulate the selectivity of electrochemical reactions with other drug compounds in order to generate oxidation products with greater selectivity and higher yield based on the optimization of cycle times and potentials. This considerably widens the scope of direct electrochemistry-based oxidation reactions for the imitation of in vivo oxidative drug metabolism.
电化学结合质谱（EC-MS）是一种新兴的分析技术，用于模拟新药开发早期的氧化药物代谢。在这里，我们展示了方波电位脉冲电化学氧化在模拟体内氧化药物代谢中的应用。我们以利多卡因（一种测试药物化合物）为例，在铂电极上进行了恒电位和方波电位脉冲氧化实验，并通过液相色谱-质谱联用（LC-MS/MS）分析了反应产物。实验结果表明，在高达+5.0 V 的恒电位下，N-脱烷基化和 4-羟基化产物的产率相对较低，而在 0.2 到 12 s 的方波电位脉冲作用下，4-羟基化产物的产率高达 50 倍（估计产率为 10%）。在方波电位脉冲作用下，当循环时间短于 0.2 s 时，N-脱烷基化产物的产率最高。因此，循环时间的调节是控制电化学氧化反应选择性的重要参数。只有在空气气氛下进行电化学氧化才能生成 N-氧化产物，这是由于电生成的过氧化氢的作用。方波电位脉冲也可用于调节其他药物化合物的电化学反应选择性，以在优化循环时间和电位的基础上，生成具有更高选择性和产率的氧化产物。这大大拓宽了基于直接电化学氧化反应模拟体内氧化药物代谢的范围。
