Strange Lauren G, Kochelek Kerri, Keasling Robert, Brown Stacy D, Pond Brooks B
Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States.
Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States.
Neurotoxicol Teratol. 2017 Sep;63:9-13. doi: 10.1016/j.ntt.2017.08.001. Epub 2017 Aug 12.
In recent years, the abuse of synthetic cathinones or 'bath salts' has become a major public health concern. Although these compounds were initially sold legally and labeled "not for human consumption", the 'bath salts' are psychostimulants, with similar structures and pharmacologic mechanisms to cocaine, the amphetamines, and 3,4 methylendioxymethamphetamine (MDMA, Molly, or Ecstasy). The reported use of these substances by women of child-bearing age highlights the necessity of studies seeking to delineate risks of prenatal exposure. Three popular drugs of this type are methylone, mephedrone, and 3, 4-methylenedioxypyrovalerone (MDPV). Unfortunately, there is currently no information available on the teratogenicity of these compounds, or of the extent to which they cross the placenta. As such, the purpose of this study was to examine the pharmacokinetic profile of the 'bath salts' in a pregnancy model. Pregnant mice (E17.5 gestation) were injected intraperitoneally with a cocktail of 5mg/kg methylone, 10mg/kg mephedrone, and 3mg/kg (MDPV) dissolved in sterile saline. Maternal brain, maternal plasma, placenta, and fetal brain were collected at 30s, 1min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 8h following injection. Methylone, mephedrone, and MDPV were extracted from tissue by solid phase extraction, and concentrations were determined using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Interestingly, all 3 cathinones reached measurable concentrations in the placenta, as well as the fetal brain; in fact, for MDPV, the maximal concentration (Cmax) was highest in fetal brain, while mephedrone's highest Cmax value was achieved in placenta. Additionally, the total drug exposure for all 3 compounds (as represented by area under the curve, AUC) was higher in fetal matrices (placenta and fetal brain) than in maternal matrices (maternal brain and plasma), and the half-lives for the drugs were longer. Given the extensive presence of methylone, mephedrone, and MDPV in the fetal brain following prenatal exposure, fetal risk is definitely a concern. As there are currently no prenatal studies available on the teratogenicity of these agents, pregnant patients should be informed about the potential risks that these substances may have.
近年来，合成卡西酮或“浴盐”的滥用已成为一个主要的公共卫生问题。尽管这些化合物最初是合法销售且标注“非供人类食用”，但“浴盐”是精神兴奋剂，其结构和药理机制与可卡因、苯丙胺以及3,4-亚甲基二氧甲基苯丙胺（摇头丸）相似。有报道称育龄女性使用这些物质，这凸显了开展研究以明确产前接触风险的必要性。这类三种常见的药物是甲酮、甲氧麻黄酮和3,4-亚甲基二氧吡咯戊酮（MDPV）。不幸的是，目前尚无关于这些化合物致畸性或其穿过胎盘程度的信息。因此，本研究的目的是在妊娠模型中检测“浴盐”的药代动力学特征。对妊娠17.5天的孕鼠腹腔注射溶解于无菌盐水中的5mg/kg甲酮、10mg/kg甲氧麻黄酮和3mg/kg MDPV的混合物。在注射后30秒、1分钟、5分钟、10分钟、15分钟、30分钟、1小时、2小时、4小时和8小时收集母鼠脑、母鼠血浆、胎盘和胎鼠脑。通过固相萃取从组织中提取甲酮、甲氧麻黄酮和MDPV，并使用先前验证的液相色谱-串联质谱（LC-MS/MS）方法测定浓度。有趣的是，所有三种卡西酮在胎盘以及胎鼠脑中均达到可测量的浓度；事实上，对于MDPV，其最高浓度（Cmax）在胎鼠脑中最高，而甲氧麻黄酮的最高Cmax值在胎盘中达到。此外，所有三种化合物的总药物暴露量（以曲线下面积，AUC表示）在胎儿基质（胎盘和胎鼠脑）中高于母鼠基质（母鼠脑和血浆），且药物的半衰期更长。鉴于产前接触后甲酮、甲氧麻黄酮和MDPV在胎鼠脑中广泛存在，胎儿风险无疑令人担忧。由于目前尚无关于这些药物致畸性的产前研究，应告知孕妇这些物质可能存在的潜在风险。
