Effect of simulated weightlessness on phase II drug metabolism in the rat

Background: Exposure to weightlessness is known to alter physiological proc esses in humans and animals. As a result of these changes, hepatic drug met abolism may be altered as well. Indeed, short term simulated weightlessness in the rat has been shown to increase oxidative metabolism. Hypothesis: Si mulated weightlessness wi II increase Phase II drug metabolism in the rat d uring short-term tail suspension. Methods: The tail-suspended rat model was used to simulate weightlessness. Rats were subjected to 1, 3, 7, or 10 d o f tail-suspension in order to mimic the effect of exposure to a microgravit y environment. One additional rat group was not suspended and served as a c ontrol. On the final day of the study, rats were administered a single intr avenous bolus dose of acetaminophen 25 mg.kg(-1) through an implanted jugul ar catheter and serial blood samples were taken for 90 min. Serum acetamino phen concentrations were measured by high-performance liquid chromatography . Pharmacokinetic parameters were determined by using standard model indepe ndent methods. Results: The results show that simulated weightlessness in t he rat has no effect on Phase II drug metabolism, using acetaminophen as a marker compound. Conclusions: These data support the hypothesis that simula ted weightlessness in the rat modulates oxidative metabolism, but not drug conjugation to glucuronide or sulfate metabolites. These data offer insight into the physiological changes and variability seen in hepatic metabolic p rofiles in humans and animals following actual spaceflight.