Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Institute of Food and Radiation Biology, Bangladesh Atomic Energy Commission, 1207 Dhaka, Bangladesh.
Chem Res Toxicol. 2022 Jun 20;35(6):1001-1010. doi: 10.1021/acs.chemrestox.2c00008. Epub 2022 May 16.
The atypical antipsychotic drugs, quetiapine and clozapine, are associated with idiosyncratic drug reactions (such as agranulocytosis or neutropenia) that are thought to involve reactive metabolites. Neutrophil myeloperoxidase (MPO) metabolism of quetiapine is not well-studied, but is metabolized by cytochrome P450. Based on structural similarity to clozapine, we hypothesized that quetiapine can be metabolized by MPO and that there is overlap between cytochrome P450 and MPO metabolism of quetiapine. The interaction of quetiapine and clozapine with MPO and MPO chlorination activity was studied using UV-vis spectrophotometry. The metabolites were characterized using liquid chromatography-mass spectrometry (LC-MS), and electron paramagnetic resonance (EPR) spectroscopy was used for detecting drug-catalyzed glutathione oxidation. In the presence of quetiapine, MPO compound II accumulated for about 7.5 min, whereas in the presence of clozapine, MPO compound II was not observed as it was rapidly reduced back to the resting state. Increasing quetiapine concentrations resulted in a decrease in MPO chlorination activity, while the opposite result was found in the case of clozapine. UV-vis spectral studies showed no change when quetiapine was oxidized in the absence and presence of chloride anion (Cl, to catalyze chlorination reactions). Significant changes, however, were observed in the same assay with clozapine, where Cl appeared to hinder the rate of clozapine metabolism. The MPO-catalyzed hydroxylated and dealkylated metabolites of quetiapine and hydroxylated metabolites of clozapine were observed from the LC-MS analyses, particularly when Cl was included in the reaction. In addition, hydroxylated, dealkylated, and a proposed sulfoxide metabolite of quetiapine were also observed in the reaction catalyzed by human microsomes/NADPH. Lastly, compared to quetiapine, clozapine metabolism by MPO/HO and glutathione produced more glutathionyl radicals using EPR spin trapping. In conclusion, MPO/HO/Cl was shown to metabolize quetiapine to S-oxidation and P450-like dealkylation products, and quetiapine metabolites were generally less reactive than clozapine.
非典型抗精神病药物喹硫平和氯氮平与独特的药物反应（如粒细胞缺乏症或中性粒细胞减少症）有关，这些反应被认为涉及反应性代谢物。喹硫平的中性粒细胞髓过氧化物酶（MPO）代谢尚未得到充分研究，但可被细胞色素 P450 代谢。基于与氯氮平的结构相似性，我们假设喹硫平可被 MPO 代谢，并且喹硫平的细胞色素 P450 和 MPO 代谢之间存在重叠。使用紫外可见分光光度法研究了喹硫平和氯氮平与 MPO 和 MPO 氯化活性的相互作用。使用液相色谱-质谱联用（LC-MS）对代谢物进行了表征，并使用电子顺磁共振（EPR）光谱法检测药物催化的谷胱甘肽氧化。在存在喹硫平的情况下，MPO 化合物 II 积累约 7.5 分钟，而在存在氯氮平的情况下，由于 MPO 化合物 II 迅速还原回静止状态，因此未观察到 MPO 化合物 II。随着喹硫平浓度的增加，MPO 氯化活性降低，而氯氮平则相反。紫外可见光谱研究表明，在不存在和存在氯离子（Cl，以催化氯化反应）的情况下，喹硫平被氧化时没有变化。然而，在相同的测定中观察到氯氮平的明显变化，其中 Cl 似乎阻碍了氯氮平代谢的速度。从 LC-MS 分析中观察到喹硫平的 MPO 催化羟基化和脱烷基代谢物以及氯氮平的羟基化代谢物，特别是当反应中包含 Cl 时。此外，在人微粒体/NADPH 催化的反应中还观察到了喹硫平的羟基化、脱烷基化和一种推测的亚砜代谢物。最后，与喹硫平相比，MPO/HO 和谷胱甘肽代谢氯氮平产生了更多的谷胱甘肽自由基，使用 EPR 自旋捕获法。总之，MPO/HO/Cl 被证明可将喹硫平代谢为 S-氧化和 P450 样脱烷基产物，并且喹硫平代谢物的反应性通常低于氯氮平。
