Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats

Recent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in different rat models of hyperlipidaemia. However, this effect is not seen after oral administration of HMG-CoA reductase inhibitors in rats. We found that oral administration of the HMG-CoA reductase inhibitor Simvastatin also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene glycol) was infused continuously for 28 days into the subcutis of control Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses which were effective in reducing cholesterol in the NAR (reductions up to -60%), reduced apolipoprotein AI but not apolipoprotein B and caused a severe inflammatory reaction in the dermis. Similar toxicity was observed in the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not cause this reaction and did not affect plasma lipids. Administration of Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. Incorporation of Simvastatin into liposomes did not diminish the toxic effect. On the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor dissolved in isotonic saline) caused no changes in the dermis and had no effect on plasma lipids in NAR or SDR. Liver microsomes prepared from the Pravastatin-treated rats demonstrated a 3- to 4-fold increase in HMG-CoA reductase activity as compared to untreated rats, confirming uptake of the drug. We conclude that continuous subcutaneous administration of the HMG-CoA reductase inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce plasma cholesterol in rats by a mechanism which is related to inhibition of HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides with, and may be related to inflammatory changes caused by administering these compounds into the dermis.

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Hepatic and nonhepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: Comparison with selected HMG-CoA reductase inhibitors

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(92)90103-3 ◽

1992 ◽

Vol 1123 (2) ◽

pp. 133-144 ◽

Cited By ~ 67

Author(s):

Thomas M.A. Bocan ◽

Erika Ferguson ◽

William McNally ◽

Paul D. Uhlendorf ◽

Sandra Bak Mueller ◽

...

Keyword(s):

Tissue Distribution ◽

Reductase Inhibitor ◽

Sterol Synthesis ◽

Hmg Coa Reductase ◽

Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

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Comparative Evaluation of the Safety and Efficacy of HMG-CoA Reductase Inhibitor Monotherapy in the Treatment of Primary Hypercholesterolemia

Annals of Pharmacotherapy ◽

10.1177/106002809502907-818 ◽

1995 ◽

Vol 29 (7-8) ◽

pp. 743-759 ◽

Cited By ~ 86

Author(s):

Irene Hsu ◽

Sarah A Spinier ◽

Nelda E Johnson

Keyword(s):

Clinical Trials ◽

Reductase Inhibitor ◽

Efficacy And Safety ◽

Comparative Efficacy ◽

Hmg Coa Reductase ◽

Primary Hypercholesterolemia ◽

Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

Objective: To evaluate the comparative efficacy and safety of the 4 currently available hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin, lovastatin, pravastatin, and simvastatin, in the treatment of primary hypercholesterolemia. Data Sources: English-language clinical studies, abstracts, and review articles identified from MEDLINE searches and bibliographies of identified articles. Unpublished data were obtained from the Food and Drug Administration in accordance with the Freedom of Information Act. Study Selection: Placebo-controlled and comparative studies of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Data Extraction: Pertinent studies were selected and the data were synthesized into a review format. Data Synthesis: The chemistry, pharmacology, and pharmacokinetics of the 4 HMG-CoA reductase inhibitors are reviewed. Clinical trials evaluating the hypocholesterolemic efficacy of the HMG-CoA reductase inhibitors are examined, and results on the comparative efficacy and safety of these agents are summarized. On a milligram-per-milligram basis, simvastatin is twice as potent as lovastatin and pravastatin. The hypocholesterolemic effects of fluvastatin appear to be approximately 30% less than that of lovastatin. In posttransplant patients receiving cyclosporine, safety has been documented for low doses of lovastatin and simvastatin, but when a higher dosage of an HMG-CoA reductase inhibitor is warranted, pravastatin should be considered the drug of choice because of a lower incidence of myopathy. Relevant data on the incidence of adverse effects are presented. Pertinent outcomes data from clinical trials evaluating the effect of HMG-CoA reductase inhibitors on atherosclerosis regression and coronary mortality, as well as published economic analyses of cholesterol-lowering agents, are summarized. Recommendations on the selection of an HMG-CoA reductase inhibitor in various clinical situations are provided. Conclusions: The literature supports the comparable safety and tolerability of all 4 currently available HMG-CoA reductase inhibitors. Therefore, the choice of an HMG-CoA reductase inhibitor should depend on the extent of cholesterol lowering needed to meet the recommended treatment goal established by the National Cholesterol Education Program. Direct comparative studies are needed to confirm the relative, long-term cost-effectiveness of the various HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia.

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Toxicity of a Novel HMG-CoA Reductase Inhibitor in the Common Marmoset (Callithrix jacchus)

Human & Experimental Toxicology ◽

10.1177/096032719401300512 ◽

1994 ◽

Vol 13 (5) ◽

pp. 357-368 ◽

Cited By ~ 7

Author(s):

K. Owen ◽

C.R. Pick ◽

S.E. Libretto ◽

M.J. Adams

Keyword(s):

Recovery Period ◽

Clinical Signs ◽

Common Marmoset ◽

Hmg Coa Reductase ◽

Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitors ◽

Chronic Study ◽

Hmg Coa Reductase Inhibitor ◽

Alveolar Proteinosis ◽

Coa Reductase

1 GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7,5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days, 2 Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes, There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3 Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4 Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5 Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6 HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.

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