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Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone Effects on iNOS mRNA Expression and Nitric Oxide During LPS-Induced Inflammation in Rats

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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.

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by grant GM24211 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy & Pharmaceutical Sciences, State University of New York at Buffalo, 565 Hochstetter Hall, Buffalo, New York, 14260, USA

    Siddharth Sukumaran, Eve-Irene Lepist, Debra C. DuBois, Richard R. Almon & William J. Jusko

  2. Department of Biological Sciences (DCD, RRA), State University of New York at Buffalo, Buffalo, New York, 14260, USA

    Debra C. DuBois & Richard R. Almon

  3. New York State Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA

    Richard R. Almon & William J. Jusko

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  1. Siddharth Sukumaran
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  2. Eve-Irene Lepist
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  3. Debra C. DuBois
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  4. Richard R. Almon
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  5. William J. Jusko
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Correspondence to William J. Jusko.

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Sukumaran, S., Lepist, EI., DuBois, D.C. et al. Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone Effects on iNOS mRNA Expression and Nitric Oxide During LPS-Induced Inflammation in Rats. Pharm Res 29, 2060–2069 (2012). https://doi.org/10.1007/s11095-012-0733-5

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  • DOI: https://doi.org/10.1007/s11095-012-0733-5

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