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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.

journal_name

Biopharm Drug Dispos

journal_title

Biopharmaceutics & drug disposition

authors

Fasanmade AA,Jusko WJ

doi

10.1002/(sici)1099-081x(199907)20:5<255::aid-bdd18

keywords:

subject

Has Abstract

pub_date

1999-07-01 00:00:00

pages

255-61

issue

eissn

0142-2782

issn

1099-081X

pii

10.1002/(SICI)1099-081X(199907)20:5<255::AID-BDD18

journal_volume

pub_type

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