Pharmacodynamic interactions between recombinant mouse interleukin-10 and prednisolone using a mouse endotoxemia model

被引:19
作者
Chakraborty, A [1 ]
Yeung, S [1 ]
Pyszczynski, NA [1 ]
Jusko, WJ [1 ]
机构
[1] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14260 USA
关键词
pharmacodynamic interaction; mouse interleukin; prednisolone; mouse model;
D O I
10.1002/jps.20257
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The pharmacodynamic interactions between recombinant mouse interleukin-10 (IL-10) and prednisolone were examined in lipopolysaccharide (LPS)-induced experimental endotoxemia in Ba1b/c mice. Treatment phases consists of single doses of IL-10 (10 mug/kg i.p.), prednisolone (25 (mg/kg i.p.), IL-10 (2.5 mug/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and IL-10 concentrations and responses to LPS including proinflammatory cytokines (TNF-alpha, IFN-gamma) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNF-alpha, IFN-gamma, 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, IL-10, 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 IL-10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNF-alpha and IFN-gamma plasma concentrations. The joint dosing of IL-10 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 IL-10 and prednisolone. (C) 2005 Wiley-Liss, Inc.
引用
收藏
页码:590 / 603
页数:14
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