The pharmacokinetics of methamphetamine self-administration in male and female rats

• Pharmacokinetic properties produce sex differences in methamphetamine (METH) self-administration.
• The model included 27 iv bolus METH doses over 120 min based on a previous study.
• Male and female rats achieved relatively stable METH concentrations within 20 min.
• Male METH concentrations were accurately predicted from pharmacokinetic simulations.
• Female METH concentrations were less predictable than male values from 60 to 180 min.

BackgroundBecause methamphetamine (METH) pharmacokinetics after single iv doses show significant differences between male and female rats, we hypothesized that pharmacokinetic differences in METH disposition could be a contributing factor to the patterns of METH self-administration behaviors in rats.MethodsFor the studies, we used a passive (non-contingent) METH dosing schedule consisting of 27 METH iv bolus injections (0.048 mg/kg) over 2 h derived from a previous active (contingent) METH self-administration behavioral study in male rats. After METH dosing of male and female Sprague-Dawley rats (n = 5/group), METH and amphetamine serum concentrations were determined by LC–MS/MS. Pharmacokinetic analysis, including predictive mathematical simulations of the data, was then conducted.ResultsMale and female rats achieved relatively stable METH serum concentrations within 20 min, which remained constant from 20 to 120 min. While not statistically different, METH clearance and volume of distribution values for females were 25% and 33% lower (respectively) than males. Linear regression analysis of predicted METH concentrations from pharmacokinetic simulations versus observed concentrations showed a substantially better correlation with male data than female data (r2 = 0.71 vs. 0.56; slope = 0.95 vs. 0.45, respectively). At 120 min, the time of predicted peak METH serum concentrations, female values were 42% higher than expected, while male values were within 3%.ConclusionsUnlike METH male pharmacokinetic data, the female data was less predictable during multiple METH administrations and produced overall higher than expected METH concentrations. These findings demonstrate that METH pharmacokinetics could contribute to differences in METH self-administration behaviors in rats.