Effect of bile duct ligation-induced liver dysfunction on methamphetamine pharmacokinetics in male and female rats

Abstract

Background: Several disease states commonly associated with methamphetamine (METH) use produce liver dysfunction, and in the bile duct ligation (BDL) model of hepatic dysfunction, rats with liver injury are more sensitive to METH effects. Additionally, both female rats and humans are known to be more sensitive to METH than males. In consideration of known sex-dependent differences in METH pharmacokinetics, this study sought to determine the potential interaction between sex and liver dysfunction variables on METH pharmacokinetics.

Methods: Sham or BDL surgery was performed on male and female rats on day 0. Serum biomarker and pharmacokinetics studies with 3 mg/kg subcutaneous (SC) METH were performed on day 7. METH-induced weight loss was measured on day 8. Liver histology evaluation and brain METH concentration measurements were performed on day 9.

Results: While BDL surgery produced significantly elevated alanine aminotransferase and bile duct proliferation in male compared to female rats, there were no significant interactions between sex and liver function in the pharmacokinetic parameters. Both liver dysfunction and female sex, however, were associated with significantly slower METH serum clearance and significantly higher brain METH concentrations (p < .05).

Conclusions: BDL-induced hepatic dysfunction produces substantial reductions in METH clearance and increased brain METH concentrations in both male and female rats, despite less liver injury in females. This preclinical model may be useful to identify and correct potential liver dysfunction comorbidity-related problems with future pharmacotherapy for stimulant use disorder with METH prior to expensive clinical trials.

Keywords: Bile duct ligation; Hepatic dysfunction; Methamphetamine; Pharmacokinetics; Rat sex.