PURPOSE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.
PURPOSE: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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.
Authors: Mitchell R McGill; David L Findley; Anna Mazur; Eric U Yee; Felicia D Allard; Allison Powers; Lori Coward; Eric R Blough; Greg Gorman; Michael D Hambuchen Journal: Eur J Drug Metab Pharmacokinet Date: 2022-02-08 Impact factor: 2.441