Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain.
Psychopharmacology (Berl). 2013 Sep;229(2):295-306. doi: 10.1007/s00213-013-3108-7. Epub 2013 May 7.
Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.
The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.
Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min.
Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α = 10.23 h(-1), β = 1.86 h(-1)). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10% and the percentage of mephedrone protein binding was 21.59 ± 3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85 ± 0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.
We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.
甲卡西酮（4-甲基甲卡西酮）是一种滥用程度较低的新型毒品，可作为摇头丸或可卡因的替代品。
本研究旨在研究甲卡西酮在大鼠体内的药代动力学和运动活性，并提供一个药代动力学/药效动力学模型。
雄性 Sprague-Dawley 大鼠分别经静脉（10 mg/kg）和口服（30 和 60 mg/kg）给予甲卡西酮。采用 LC/MS 和 LC-MS/MS 碎裂模式对血浆浓度和代谢物进行了特征分析。监测了 180-240 分钟的运动活性。
静脉给予甲卡西酮后，其血浆浓度符合二室模型（α=10.23 h(-1)，β=1.86 h(-1)）。口服给药后，甲卡西酮的血药峰浓度在 0.5-1 小时之间达到，9 小时后降至无法检测水平。甲卡西酮的绝对生物利用度约为 10%，蛋白结合率为 21.59±3.67%。我们在大鼠口服给药后的血液中鉴定出了 5 种 I 相代谢物。脑水平与游离血浆浓度之间的关系为 1.85±0.08。甲卡西酮诱导的运动活性呈剂量依赖性增加，持续时间长达 2 小时。药代动力学-药效动力学模型成功描述了甲卡西酮血浆浓度与其精神刺激作用之间的关系。
我们推测，甲卡西酮口服后存在非常重要的首过效应，并且容易进入中枢神经系统。所描述的模型可能有助于估计和预测甲卡西酮药效动力学的起始、幅度和时间过程，以及设计新的甲卡西酮成瘾和毒性动物模型。
