Pharmacokinetics of α-Pyrrolidinovalerophenone in Male Rats with and without Vaccination with an α-Pyrrolidinovalerophenone Vaccine.
Pharmacokinetics of α-Pyrrolidinovalerophenone in Male Rats with and without Vaccination with an α-Pyrrolidinovalerophenone Vaccine.
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DOI：
10.18433/jpps31832
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Owens M
中科院分区：
文献类型：
--
作者：
McClenahan S;Gunnell M;Owens M
α-吡咯烷基戊酮（α-PVP）是第二代合成卡西酮，其作为脑中多巴胺和去甲肾上腺素转运体的抑制剂。这些新研究确定了α-PVP在大鼠中的药代动力学（PK），然后评价了α-PVP疫苗对PK特征的影响。将成年雄性Sprague-Dawley大鼠随机分为治疗组（n = 24只/组），其中接种大鼠在第0、3和9周接受α-PVP疫苗的初始免疫和两次加强免疫。对照大鼠接受盐水注射。然后在11-12周期间向两组给予α-PVP（0.56、1、3 mg/kg，皮下），并收集血清样本，通过LC-MS/MS测定α-PVP血清浓度（n=6只大鼠/处理/时间）。在13周时，给予1 mg/kg α-PVP后，通过LC-MS/MS测定脑、心脏和肾脏中α-PVP的浓度（n=4-5只大鼠/处理/时间）。对照大鼠的PK值显示最大血清浓度（Cmax）和曲线下面积（AUCinf）值呈剂量依赖性增加，消除半衰期（t1/2）约为2.1 h。α-PVP在对照大鼠中表现出线性PK特征。接种疫苗的大鼠的血清Cmax和AUCinf值显着（p<0.05）高于对照组，并显着降低全身清除率、分布容积和t1/2值。在早期时间点，与对照组大鼠相比，接种组大鼠脑、心脏和肾脏中的α-PVP浓度显著较低。与对照组相比，接种新型α-PVP疫苗显著改变了血清PK，导致脑、肾和心脏α-PVP浓度呈时间依赖性降低。
α-Pyrrolidinovalerophenone (α-PVP) is a second-generation synthetic cathinone which acts as an inhibitor at the dopamine and norepinephrine transporters in the brain. These novel studies determined the pharmacokinetics (PK) of α-PVP in rats and then evaluated the effects of an α-PVP vaccine on the PK profile. Adult male Sprague-Dawley rats were randomly divided into treatment groups (n = 24/group) in which the vaccinated rats received an initial and two booster immunizations of the α-PVP vaccine at 0, 3, and 9 wks. Control rats received saline injections. α-PVP (0.56, 1, 3 mg/kg, sc) was then administered to both groups between 11–12 weeks and serum samples were collected for determination of α-PVP serum concentrations by LC-MS/MS (n=6 rats/treatment/time). At 13 weeks, brain, heart and kidney concentrations of α-PVP were determined by LC-MS/MS after administration of 1 mg/kg α-PVP (n=4–5 rats/treatment/time). PK values in control rats showed dose-dependent increases in maximum serum concentrations (Cmax) and area under the curve (AUCinf) values with an elimination half-life (t1/2) of approximately 2.1 h. α-PVP exhibited linear PK profile in control rats. Vaccinated rats had significantly (p<0.05) higher serum Cmax and AUCinf values than controls, and significantly reduced total body clearance, volume of distribution and t1/2 values. Vaccinated rats had significantly lower α-PVP concentrations in the brain, heart, and kidney in comparison to control rats at early time points. Vaccination with the novel α-PVP vaccine significantly altered serum PK leading to a time-dependent reduction in brain, kidney and heart concentrations of α-PVP compared to controls.
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