Effects of Simulated Weightlessness on Metabolizing Enzymes and Zolpidem Pharmacokinetics in SD rats
Abstract
Zolpidem is a known hypnotic for astronauts in spaceflight. Up until now, the effect of microgravity on the pharmacokinetics of zolpidem remained unclear. The pharmacokinetics of zolpidem in SD rats were studied under both short-term and long-term simulated weightlessness, laying the foundation for safe administration to astronauts. The plasma concentration-time profile of orally administered zolpidem in normal or tail-suspended SD rats was acquired by LC-MS/MS. The pharmacokinetic parameters AUC and Cmax were the lowest for two-week tail suspension. The Tmax for the tail-suspension groups was higher than for the CON group. The mRNA and protein expression levels of CYP3A1, a zolpidem metabolic enzyme, were measured in a variety of organs by Western blotting and RT-PCR over four suspension times (SUS-7d, SUS-14d, SUS-21d, and SUS-28d). CYP3A1 levels were increased in the liver and kidney after SUS-14d. In contrast, CYP3A1 levels significantly decreased in the duodenum and jejunum at this time point. The simulated microgravity of SD rats exhibited an unequivocal reduction in zolpidem bioavailability and effect on CYP3A1 expression in a variety of tissues.
