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 e ssential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic ac id production. In three separate studies, oral administration of fluva statin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation t hrough weaning resulted in unanticipated maternal mortality at the tim e of parturition and during lactation. Microscopic evaluations perform ed in two studies revealed significant cardiac myopathy in the dying a nimals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were al so noted at one or both dose levels. Supplementation of fluvastatin ad ministration with 500 mg/kg b.i.d. of mevalonic acid completely blocke d and/or ameliorated the mortality, cardiac myopathy, and other advers e effects. These studies indicate that the adverse maternal effects ob served 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. (C) 1994 Wiley-Liss, Inc .