Immunodynamics of methylprednisolone induced T-cell trafficking and deactivation using whole blood lymphocyte proliferation techniques in the rat

Glucocorticoids have diverse effects on various components of the immune sy stem and assessment of such activities in vivo often involves complex techn iques and numerous animals. We developed a whole blood technique for determ ining proliferation rate of lymphocytes in minute amounts of rat blood (5 m u L as opposed to a whole rat spleen) (Fasanmade AA, Jusko WJ. J Immunol Me thods 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-lymphocy te trafficking between vascular and extravascular pools. Blood samples were taken over several hours after iv MP administration to adrenalectomized ra ts, MP concentrations and lympho-proliferative activities were determined e x 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 pharmacod ynamics (PD) of T-cell trafficking was modeled with a physiological indirec t model to generate the IC50 (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 brood T-cells was modeled with an equation which ac counts directly for inhibition of the proliferation activity of available b lood T-cells with an DC50 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 wit h a nadir at 4 h, and return to baseline by 9 h. Lymphocyte deactivation oc curred within minutes of MP infusion and returned to baseline in 9 h. MP ac tion was prolonged owing to the low IC50. This approach for assessing dual features of corticosteroid effects on T-cell trafficking and deactivation a llows quantitative PK/PD modeling in small animals such as the rat. Copyrig ht (C) 1999 John Wiley & Sons, Ltd.