Modeling of corticosteroid effects on hepatic low-density lipoprotein receptors and plasma lipid dynamics in rats.
OBJECTIVE
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.


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.
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
A
Hazra
Nancy A
NA
Pyszczynski
Debra C
DC
DuBois
Richard R
RR
Almon
William J
WJ
Jusko
D000818:Animals; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002940:Circadian Rhythm; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007273:Injections, Intramuscular; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008776:Methylprednisolone Hemisuccinate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005938:Glucocorticoids; D008055:Lipids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011973:Receptors, LDL; D014280:Triglycerides; D008776:Methylprednisolone Hemisuccinate; D002784:Cholesterol