Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, Huntington, WV, USA. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
J Pharm Pharm Sci. 2019;22(1):301-312. doi: 10.18433/jpps30471.
Methamphetamine (METH) abuse is associated with hepatic dysfunction related comorbidities such as HIV, hepatitis C, and polysubstance abuse with acetaminophen-containing opioid formulations. We aimed to develop a bile duct ligation (BDL)-induced hepatic dysfunction model for studying both METH and experimental treatments for METH abuse in this comorbidity.
Sham or BDL surgery was performed in male Wistar rats on day 0. Liver function was measured throughout the study. On days 7 and 19, serum pharmacokinetics studies were performed with 1 mg/kg subcutaneous (sc) METH. On day 21, this dose was repeated to determine 2 h post-METH brain concentrations. METH-induced open field behaviors were measured every other day (days 12 - 16) with ascending sc doses (0.3 - 3 mg/kg).
BDL transiently increased alanine aminotransferase levels and altered liver structure, which resulted in significantly greater METH serum and brain exposure. In the BDL compared to sham group, there was a longer duration of METH-induced locomotor activity (after 1 and 3 mg/kg) and stereotypy (after 3 mg/kg).
In rats, liver dysfunction reduced METH clearance, increased brain METH concentrations, and enhanced METH effects on locomotor activity in a dose dependent manner. In addition, this model could be further developed to simulate the associated hepatic dysfunction of key METH abuse comorbidities for preclinical testing of novel pharmacotherapies for effectiveness and/or toxicity in vulnerable populations.
甲基苯丙胺（METH）滥用与肝功能障碍相关的合并症有关，如 HIV、丙型肝炎和包含对乙酰氨基酚的阿片制剂的多种物质滥用。我们旨在建立一种胆管结扎（BDL）诱导的肝功能障碍模型，以研究 METH 及其在这种合并症中的实验治疗方法。
在雄性 Wistar 大鼠第 0 天进行假手术或 BDL 手术。在整个研究过程中测量肝功能。在第 7 天和第 19 天，进行 1mg/kg 皮下（sc）METH 的血清药代动力学研究。在第 21 天，重复该剂量以确定 METH 后 2 小时的脑浓度。每隔一天（第 12 天至第 16 天）用递增的 sc 剂量（0.3-3mg/kg）测量 METH 诱导的旷场行为。
BDL 短暂性地增加了丙氨酸氨基转移酶的水平并改变了肝结构，导致 METH 血清和脑暴露显著增加。与假手术组相比，BDL 组中 METH 诱导的运动活性（1 和 3mg/kg 后）和刻板行为（3mg/kg 后）持续时间更长。
在大鼠中，肝功能障碍降低了 METH 的清除率，增加了脑内 METH 浓度，并以剂量依赖的方式增强了 METH 对运动活性的作用。此外，该模型可以进一步发展，以模拟关键 METH 滥用合并症相关的肝功能障碍，用于新的药理学治疗方法在易受影响人群中的有效性和/或毒性的临床前测试。
