Prevention of fluvastatin-induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation.
Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.
Hrab
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Drug Safety Department, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey 07936.
Hartman
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Cox
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D000704:Analysis of Variance; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D002784:Cholesterol / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005260:Female; D005298:Fertility / Q000187:drug effects; D005313:Fetal Death / Q000517:prevention & control; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008098:Litter Size; D008798:Mevalonic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D007744:Obstetric Labor Complications / Q000401:mortality / Q000517:prevention & control; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced / Q000517:prevention & control*; D011644:Puerperal Disorders / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D002784:Cholesterol; D008798:Mevalonic Acid