Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8994337 | Journal of Pharmaceutical Sciences | 2005 | 14 Pages |
Abstract
The pharmacodynamic interactions between recombinant mouse interleukinâ10 (ILâ10) and prednisolone were examined in lipopolysaccharide (LPS)âinduced experimental endotoxemia in Balb/c mice. Treatment phases consists of single doses of ILâ10 (10 μg/kg i.p.), prednisolone (25 (mg/kg i.p.), ILâ10 (2.5 μg/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and ILâ10 concentrations and responses to LPS including proinflammatory cytokines (TNFâα, IFNâγ) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNFâα, IFNâγ, and NO concentrations. Noncompartmental and model fitting using extended indirect response models based on drug inhibition of multiphase stimulation of biomarkers by LPS were used to describe the in vivo pharmacodynamics and drug interactions. Dosing with prednisolone, ILâ10, or their combinations produced strong inhibition of cytokine and NO production. The IC50 values of prednisolone ranged from 54 to 171 ng/mL, and IC50 values for ILâ10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNFâα and IFNâγ plasma concentrations. The joint dosing of ILâ10 with prednisolone produces moderately synergistic immunosuppressive effects in this system. Both drugs were sufficiently protective in suppressing the inflammatory mediators when administered prior to the LPS trigger, while such effects were modest when administered after the inflammatory stimulus was provoked. The integrated and complex pharmacokinetic/pharmacodynamic models well capture the in vivo processes, drug potencies, and interactions of ILâ10 and prednisolone. © 2005 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 94:590-603, 2005
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Authors
Abhijit Chakraborty, Sally Yeung, Nancy A. Pyszczynski, William J. Jusko,