Pharmacokinetic/pharmacodynamic modeling of methylprednisolone effects on iNOS mRNA expression and nitric oxide during LPS-induced inflammation in rats.

Abstract

PURPOSE:

Increased expression of inducible nitric oxide synthase (iNOS) resulting in nitric oxide elevation represents an important component of inflammatory responses. We assess the effects of methylprednisolone (MPL) on these processes during endotoxin-induced acute inflammation and provide a mechanism-based model to quantitatively describe them.

METHODS:

Male Lewis rats were dosed with lipopolysaccharide (50 μg/kg LPS) alone or with methylprednisolone (10 and 50 mg/kg) and sacrificed at different time points. Plasma MPL, lung iNOS mRNA expression, plasma nitric oxide (NO) and other physiological factors were measured. Sodium nitrate (750 μmole/kg) was given to a separate cohort of rats to assess NO disposition kinetics. PK-PD modeling was performed with ADAPT 5.

RESULTS:

Disposition kinetics of plasma MPL and NO showed bi-exponential decline and were described by two-compartment models. LPS increased expression of iNOS mRNA in lung and increased plasma NO, while MPL dosing palliated this increase in a dose-dependent manner. These effects were well captured using tandem indirect response and precursor-pool models.

CONCLUSION:

The model provides a quantitative assessment of the suppression of NO production by MPL and shows that the major effects are at the transcriptional level by reducing expression of iNOS mRNA.

• Authors: Siddharth Sukumaran, Eve-Irene Lepist, Debra C DuBois, Richard R Almon, William J Jusko
• Journal: Pharmaceutical research (Pharm Res) Vol. 29 Issue 8 Pg. 2060-9 (Aug 2012) ISSN: 1573-904X [Electronic] United States
• PMID: 22422321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents
• Lipopolysaccharides
• RNA, Messenger
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Methylprednisolone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacokinetics, pharmacology)
• Gene Expression Regulation (drug effects)
• Inflammation (drug therapy, immunology)
• Lipopolysaccharides (immunology)
• Male
• Methylprednisolone (pharmacokinetics, pharmacology)
• Models, Biological
• Nitric Oxide (immunology)
• Nitric Oxide Synthase Type II (genetics, immunology)
• RNA, Messenger (genetics, immunology)
• Rats
• Rats, Inbred Lew