Pharmacokinetic/pharmacodynamic modeling of methylprednisolone effects on iNOS mRNA expression and nitric oxide during lpsinduced inflammation in rats

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 endotoxininduced 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 biexponential 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.