Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY, USA.
Designer Drug Research Unit, Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, MD, USA.
Curr Pharm Des. 2022;28(32):2653-2663. doi: 10.2174/1381612828666220907100036.
MDPV (3,4-methylenedioxypyrovalerone) is a synthetic stimulant that blocks transmitter uptake at transporters for dopamine and norepinephrine. Less is known about MDPV pharmacokinetics, especially with respect to brain concentrations of the drug and its metabolites.
The goal of the present study was: 1) to determine brain concentrations of MDPV and its metabolites, 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxy-pyrovalerone (4-OH-3-MeOPV), after administration of MDPV, and 2) to relate brain pharmacokinetic measures to pharmacodynamic endpoints in the same subjects.
Male Sprague-Dawley rats (300-400 g) received s.c. MDPV injection (1, 2, or 4 mg/kg) or its saline vehicle. Groups of rats were decapitated at 40 min and 240 min postinjection. Locomotor behavior was rated before decapitation, and the core temperature was obtained. Plasma and frontal cortex were analyzed to quantitate MDPV and its metabolites. Striatal samples were analyzed to measure dopamine, serotonin (5-HT), and their metabolites.
MDPV displayed brain-to-plasma ratios greater than 1 (range 8.8-12.1), whereas 3,4-catechol-PV and 4-OH-3-MeO-PV showed ratios less than 1 (range 0-0.3). MDPV increased behavioural scores reflective of locomotor stimulation at 40 and 240 min and produced slight hyperthermia at 240 min. MDPV had no effect on striatal dopamine but produced an increase in the metabolite homovanillic acid (HVA). Brain MDPV concentrations were positively correlated with behavioural scores and striatal HVA but not with other endpoints.
The behavioural effects of MDPV are related to brain concentrations of the parent drug and not its metabolites. The modest effects of MDPV on monoamine systems suggest that other non-monoamine mechanisms may contribute to the effects of the drug in vivo.
MDPV（3,4-亚甲二氧基吡咯戊酮）是一种合成兴奋剂，可阻断多巴胺和去甲肾上腺素转运体对递质的摄取。对于 MDPV 的药代动力学，特别是关于药物及其代谢物在大脑中的浓度，了解较少。
本研究的目的是：1）确定 MDPV 给药后 MDPV 及其代谢物 3,4-二羟基吡咯戊酮（3,4-儿茶酚-PV）和 4-羟基-3-甲氧基-吡咯戊酮（4-OH-3-MeOPV）在大脑中的浓度，2）将大脑药代动力学参数与同一受试者的药效学终点相关联。
雄性 Sprague-Dawley 大鼠（300-400g）接受皮下 MDPV 注射（1、2 或 4mg/kg）或其生理盐水载体。注射后 40 分钟和 240 分钟，各组大鼠断头。断头前对运动行为进行评分，并测定核心体温。分析血浆和前额皮质以定量 MDPV 及其代谢物。纹状体样本用于测量多巴胺、血清素（5-HT）及其代谢物。
MDPV 显示出大于 1 的脑/血浆比值（范围 8.8-12.1），而 3,4-儿茶酚-PV 和 4-OH-3-MeO-PV 的比值小于 1（范围 0-0.3）。MDPV 在 40 分钟和 240 分钟时增加了反映运动刺激的行为评分，并在 240 分钟时产生轻微的体温升高。MDPV 对纹状体多巴胺没有影响，但增加了代谢物高香草酸（HVA）。大脑 MDPV 浓度与行为评分和纹状体 HVA 呈正相关，但与其他终点无关。
MDPV 的行为效应与大脑中母体药物的浓度有关，而不是其代谢物。MDPV 对单胺系统的适度影响表明，其他非单胺机制可能有助于药物在体内的作用。
