title: Immunodynamics of methylprednisolone induced T-cell trafficking and deactivation using whole blood lymphocyte proliferation techniques in the rat.
abstract: Glucocorticoids have diverse effects on various components of the immune system and assessment of such activities in vivo often involves complex techniques and numerous animals. We developed a whole blood technique for determining proliferation rate of lymphocytes in minute amounts of rat blood (5 microL as opposed to a whole rat spleen) (Fasanmade AA, Jusko WJ. J Immunol Methods 1995; 184: 163-167). This method was used in assessment of in vivo T-cell deactivation by methylprednisolone (MP). The blockade of this process by the anti-glucocorticoid, RU 40555, also allows measurement of T-lymphocyte trafficking between vascular and extravascular pools. Blood samples were taken over several hours after iv MP administration to adrenalectomized rats, MP concentrations and lympho-proliferative activities were determined ex vivo after mitogen activation with and without blocking MP with RU 40555. MP disposition was mono-exponential with a t(1/2) of 34 min. The pharmacodynamics (PD) of T-cell trafficking was modeled with a physiological indirect model to generate the IC(50) (0.4 ng/mL) for the inhibitory action of MP on return of T-cells to blood as well as cell trafficking rate constants. The overall suppression of blood T-cells was modeled with an equation which accounts directly for inhibition of the proliferation activity of available blood T-cells with an DC(50) of 0.37 ng/mL. MP produced an initial influx of T-cells to blood within 1 h of infusion, a later marked T-cell depletion with a nadir at 4 h, and return to baseline by 9 h. Lymphocyte deactivation occurred within minutes of MP infusion and returned to baseline in 9 h. MP action was prolonged owing to the low IC(50). This approach for assessing dual features of corticosteroid effects on T-cell trafficking and deactivation allows quantitative PK/PD modeling in small animals such as the rat.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 565 Hochstetter Hall, Buffalo, NY 14260, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Fasanmade
authors.forename: W J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics / Q000494:pharmacology*; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; C075646:RU 40555; D015735:Mifepristone; D008775:Methylprednisolone