Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus N, Denmark.
Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, DK-8000, Aarhus C, Denmark.
Arch Toxicol. 2024 Jan;98(1):289-301. doi: 10.1007/s00204-023-03620-2. Epub 2023 Oct 23.
Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225-296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.
药物代谢动力学和内源性代谢物的变化可能是抗精神病药和阿片类药物同时使用产生附加生物学效应的基础。在这项研究中，我们采用非靶向代谢组学分析和靶向分析方法，研究了喹硫平和美沙酮急性联合给药后大鼠前额叶皮层（PFC）、中脑和血液中药物代谢物和内源性代谢物的变化。大鼠分为四组，分别接受累积递增剂量的喹硫平（QTP）、美沙酮（MTD）、喹硫平+美沙酮（QTP+MTD）或载体（对照）。所有样本均采用液相色谱-质谱联用（LC-MS）进行分析。我们的研究结果表明，当美沙酮存在时，血液和大脑中喹硫平的代谢物：去甲喹硫平、O-去烷基喹硫平、7-羟基喹硫平、喹硫平亚砜的水平升高。我们的研究还表明，当存在喹硫平时，大鼠大脑中美沙酮及其代谢物 2-乙基-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）的水平下降。尽管存在这些发现，但由于联合给药与单一给药相比，只有少数内源性代谢物（225-296）的水平存在较小差异。例如，同时给予两种化合物可使大鼠大脑中 N-甲基谷氨酸、戊二酸、对羟基苯乳酸和皮质酮的水平显著降低。此外，在 MTD 组中还观察到中脑中 5-羟色胺的积累，但在 QTP+MTD 组中没有观察到。总之，这项大鼠研究表明，喹硫平和美沙酮同时使用时会产生一些但很重要的附加代谢效应。
