Influence of gender on prednisolone effects on whole blood T-cell deactivation and trafficking in rats

Prednisolone (5 mg/kg intravenous) was administered to adrenalectomized mal e and female Sprague-Dawley rats (250-350 g) to assess the effects of gende r on disposition and pharmacoimmunodynamics. Plasma concentrations of predn isolone were determined by high-performance liquid chromatography. Incorpor ation of PH]thymidine (H-3-TDR) was used to determine whole blood T-cell (W BTC) trafficking and deactivation following stimulation with Concanavalin-A . Whole blood T-cell trafficking was determined indirectly by using the glu cocorticoid receptor antagonist RU-40555 (250 ng/mL) added to ex vivo cultu res of whole blood from animals dosed with prednisolone. Mean +/- SD) predn isolone clearance values were 3.22 +/- 0.88 and 3.46 +/- 0.96 L/h/kg in mal es and females, respectively. After administration of prednisolone, relativ e T-cell counts decreased slowly with time to reach a nadir at 3-5 h and re turned to baseline levels by 8 h. Fitting data using an indirect response m odel yielded mean prednisolone 50% inhibitory concentration for inhibition of WBTC trafficking (IC50T) that was lower in males compared with females ( 0.14 +/- 0.16 versus 1.03 +/- 0.06 ng/mL; p < 0.05). In the absence of RU-4 0555, an immediate and complete inhibition of 3H-TDR incorporation into WBT C was observed (deactivation) and baseline levels were recovered slowly as prednisolone was cleared from blood. The mean 50% inhibitory concentration for inhibition of WBTC deactivation (IC50D) based on an inhibitory I-max mo del was similar in males and females (0.20 +/- 0.24 versus 0.18 +/- 0.12 ng /mL). Although male and female rats have similar exposure to prednisolone a fter 5-mg/kg doses, males are more sensitive to the inhibition of WBTC traf ficking, whereas no gender effects on deactivation of WBTC exist.