Radiation Effects on Methamphetamine Pharmacokinetics and Pharmacodynamics in Rats.

BACKGROUND AND OBJECTIVES: Whole-body radiation exposure has been shown to alter the pharmacokinetics of certain drugs in both animal models and humans, but little is known about the effect of radiation on psychoactive medications. These drugs may have altered pharmacokinetics when administered during or after space travel or therapeutic or accidental radiation exposure, resulting in reduced efficacy or increased toxicity. METHODS: Methamphetamine was used to determine the effects of acutely administered 1, 3, and 6 Gy radiation on drug pharmacokinetics and pharmacodynamics. Male Wistar rats were exposed to 0, 1, 3, or 6 Gy X-ray radiation on day 0. The serum pharmacokinetics of subcutaneously administered 1 mg/kg methamphetamine was determined on day 3. Methamphetamine-induced (1 mg/kg) locomotor activity was measured on day 5. Brain methamphetamine concentrations were determined 2 h after methamphetamine administration (1 mg/kg) on day 6. Renal and hepatic serum biomarkers were assessed on days 3 and 6, with liver histology performed on day 6. RESULTS: While serum half-life and unchanged methamphetamine urine clearance were unaffected by any radiation dose, maximum methamphetamine concentrations and methamphetamine and amphetamine metabolite area under the serum concentration-time curve values from 0 to 300 min were significantly reduced after 6 Gy radiation exposure. Additionally, methamphetamine-induced locomotor activity and the brain to serum methamphetamine concentration ratio were significantly elevated after 6 Gy radiation. CONCLUSIONS: While 1-6 Gy radiation exposure did not affect methamphetamine elimination, 6 Gy exposure had effects on both subcutaneous absorption and brain distribution. These effects should be considered when administering drugs during or after radiation exposure.

Methamphetamine-Induced Open Field Behavior and LD50 in Periplaneta americana Cockroaches (Blattodea: Blattidae).

Invertebrate animal studies of methamphetamine (METH) could allow for high throughput, inexpensive, and high-animal number pharmacology and toxicology studies. We hypothesized that in Periplaneta americana cockroaches, METH would increase locomotion compared to saline and produce lethality. Lethal dose, 50% (LD50) was determined with 0-1,780 µg/g (mg/kg) METH (n = 15-16/group) using logit analysis. Locomotor activity after METH (0-560 mg/kg, intra-abdominal, n = 8 per group) administration and spontaneous locomotor activity in surviving cockroaches in an open field 24 h after LD50 study doses was measured with Noldus Ethovision. The LD50 of METH was 823.1 mg/kg (more than 10-fold greater than the value in rats). There were significant decreases in spontaneous locomotor activity in surviving cockroaches after administration of 650 and 750 mg/kg METH (P < 0.05). While 100 mg/kg METH did not significantly increase METH locomotor activity relative to saline, 300 mg/kg METH significantly increased locomotor activity compared to saline (P < 0.05), and 560 mg/kg METH resulted in most of the cockroaches slowly moving around the open field in the supine position for most of the trial. In conclusion, METH produces pharmacological and toxicological effects in P. americana. The high availability, low cost, and relative ease of use of these animals makes them a potential, very accessible option for studying METH use disorder.

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

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.