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 male and female Sprague-Dawley rats (250-350 g) to assess the effects of gender on disposition and pharmacoimmunodynamics. Plasma concentrations of prednisolone were determined by high-performance liquid chromatography. Incorporation of [3H]thymidine (3H-TDR) was used to determine whole blood T-cell (WBTC) trafficking and deactivation following stimulation with Concanavalin-A. Whole blood T-cell trafficking was determined indirectly by using the glucocorticoid receptor antagonist RU-40555 (250 ng/mL) added to ex vivo cultures of whole blood from animals dosed with prednisolone. Mean (+/- SD) prednisolone clearance values were 3.22 +/- 0.88 and 3.46 +/- 0.96 L/h/kg in males and females, respectively. After administration of prednisolone, relative T-cell counts decreased slowly with time to reach a nadir at 3-5 h and returned to baseline levels by 8 h. Fitting data using an indirect response model 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-40555, an immediate and complete inhibition of 3H-TDR incorporation into WBTC 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 Imax model 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 after 5-mg/kg doses, males are more sensitive to the inhibition of WBTC trafficking, whereas no gender effects on deactivation of WBTC exist.
Meno-Tetang
G M
GM
Bioanalytical R & D, Wyeth-Ayerst Research, Pearl River, New York 10965, USA.
Gobburu
J V
JV
Jusko
W J
WJ
D000315:Adrenalectomy; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D008954:Models, Biological; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013601:T-Lymphocytes / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism
D006727:Hormone Antagonists; C075646:RU 40555; D015735:Mifepristone; D011239:Prednisolone; D013936:Thymidine