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Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats

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Abstract

Purpose

This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis.

Materials and methods

Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG).

Results

MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols.

Conclusions

Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future.

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Abbreviations

ADX:

adrenalectomized

CS:

corticosteroids

CST:

corticosterone

DR:

drug-receptor complex

DR(N):

nuclear drug-receptor complex.

GR:

glucocorticoid receptor

HDLC:

high-density lipoprotein cholesterol

LDLC:

low-density lipoprotein cholesterol

LDLR:

low-density lipoprotein receptors

MPL:

methylprednisolone

PD:

pharmacodynamics

PK:

pharmacokinetics

RT-PCR:

reverse transcription polymerase chain reaction

TC:

total cholesterol

TG:

triglycerides

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Acknowledgement

This study was supported by Grant no. GM 24211 from the National Institutes of Health.

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Authors and Affiliations

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

    Anasuya Hazra, Nancy A. Pyszczynski, Debra C. DuBois, Richard R. Almon & William J. Jusko

  2. Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, 14260, USA

    Debra C. DuBois & Richard R. Almon

  3. Department of Clinical Pharmacology, Infectious Diseases, Pfizer Inc., New London, Connecticut, 06380, USA

    Anasuya Hazra

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  1. Anasuya Hazra
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  2. Nancy A. Pyszczynski
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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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Hazra, A., Pyszczynski, N.A., DuBois, D.C. et al. Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats. Pharm Res 25, 769–780 (2008). https://doi.org/10.1007/s11095-007-9371-8

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  • DOI: https://doi.org/10.1007/s11095-007-9371-8

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