The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.