Gender differences in pharmacokinetics of antipyrine in a simulated weightlessness rat model

Abstract

Background: Gender differences in gastrointestinal physiology and hepatic metabolizing enzyme systems may potentially modify drug absorption and disposition during spaceflight. This study evaluated the effect of simulated weightlessness on gender-related pharmacokinetic differences of intravenously administered antipyrine, a marker compound for hepatic oxidative metabolism, using the tail-suspended (TS) rat model for microgravity. Methods: TS rats were suspended at a 45° angle from the cage floor for 3 d prior to and for 8 h after antipyrine administrations. Control and TS jugular vein-cannulated male and female Sprague-Dawley rats received a 20 mg z kg -1 intravenous dose of antipyrine. Serial blood samples (0.25 ml) were collected from each rat at 14 predetermined times. Plasma drug concentrations were measured by a HPLC method. Plasma antipyrine concentration-time data were analyzed using noncompartmental pharmacokinetic methods. Statistical comparisons were made using the nonparametric Mann-Whitney U-test. Results: In male rats, simulated weightlessness appreciably and significantly reduced the mean total body clearance of antipyrine by 44.7% and increased the mean residence time of antipyrine by 58.3%, but had no significant effect on the apparent volume of distribution of the drug. In striking contrast to that observed in male rats, simulated weightlessness had no significant effect on the disposition kinetics of antipyrine in female rats. Conclusion: Significant gender difference exists in microgravity-induced changes in drug disposition, where simulated weightlessness apparently has more of an effect in male versus female rats in terms of hepatic enzymatic functions. © by the Aerospace Medical Association, Alexandria, VA.