Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

Ohtawa, Masakatsu; Masuda, Naoki; Karasawa, Yoshio; Tojo, Hitomi

doi:10.1007/bf03189669

European Journal of Drug Metabolism and Pharmacokinetics

1995

DOI: 10.1007/bf03189669

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Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

Masakatsu Ohtawa¹,

Naoki Masuda²,

Yoshio Karasawa³

et al.

Abstract: Fluvastatin (FV), a new cholesterol-lowering agent, has been studied for its effects on hepatic microsomal drug-metabolizing enzymes in male rats. FV was orally administered in dosages of 1, 5, and 30 mg/kg/day for 7 consecutive days. 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activities were markedly decreased at all dose levels. The amount of microsomal protein and the contents of cytochromes P450 and b5 did not change. No induction of aniline hydroxylase, aminopyrine N-demethylase, testosterone hydr… Show more

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Cited by 2 publications

References 26 publications

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Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels

Spieker

Noll²,

Hannak³

et al. 2000

Journal of Cardiovascular Pharmacology

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Hyperlipidemia is an important cardiovascular risk factor. Lipid-lowering therapy has been shown to decrease morbidity and mortality in these patients. Combination therapy with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and a fibric-acid derivative has been reported to be more efficacious to reduce low-density lipoprotein (LDL) cholesterol and triglycerides but may be associated with an increased risk of myositis. The aim of this study was to investigate the efficacy and tolerability of fluvastatin, an HMG-CoA reductase inhibitor, alone and in combination with bezafibrate, a fibric-acid derivative. In a randomized controlled trial with 454 hypercholesterolemic patients (mean cholesterol, 8.6 +/- 1.6 mM), fluvastatin (20 mg/day) significantly lowered total plasma cholesterol levels (-12.5%; p < 0.0001 vs. placebo), LDL cholesterol (-14%; p < 0.0001), and triglycerides (-4%; p = 0.05). A small increase in high-density lipoprotein (HDL) cholesterol levels (3%, NS) also was observed. Combination therapy with fluvastatin and bezafibrate (400 mg/day) in 71 patients with persistent hypertriglyceridemia during treatment with the statin resulted in a more pronounced reduction in triglyceride (-47%; p < 0.0001) and total cholesterol levels (-15%; p < 0.0001) than did fluvastatin alone. Furthermore, the additional bezafibrate significantly increased HDL cholesterol (+5%; p < 0.001). No significant increases in creatine phosphokinase levels or in frequency of myalgia were observed. In summary, fluvastatin decreases both cholesterol and triglyceride levels. In patients with persistent hypertriglyceridemia, combination therapy with fluvastatin and bezafibrate may be safely used to lower triglyceride and cholesterol levels more efficiently.

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Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels

Spieker

Noll²,

Hannak³

et al. 2000

Journal of Cardiovascular Pharmacology

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Preclinical Development of New Drugs that Enhance Thyroid Hormone Metabolism and Clearance: Inadequacy of Using Rats as an Animal Model for Predicting Human Risks in an IND and NDA

Wu¹,

Farrelly²

2006

American Journal of Therapeutics

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New drugs that enhance metabolism or clearance of thyroid hormones in rats often trigger a sequence of toxicity events during chronic administration: reduction of thyroxine, elevation of thyroid-stimulating hormone (TSH) levels, and thyroid gland hyperfunction/growth. Hepatocellular hypertrophy and thyroid follicular hyperplasia are often observed with increased liver and thyroid organ weights. This unique toxicity profile seems to be species-specific because the thyroxine in rodents is metabolized rapidly, without thyroid hormone-binding globulin that serves as a reserve, as in humans. Thus, elevations of TSH were not reported in humans for drugs such as delavirdine, fluvastatin, nicardipine, phenobarbital, simvastatin, and spironolactone, all of which produce thyroid hyperplasia or tumors in rats. Further, the human thyroid is less sensitive to prolonged TSH stimulation than that of the rat (eg, endemic goiter patients with high TSH due to iodine deficiency do not develop thyroid cancer). In view of the species difference in sensitivity of the thyroid between rodents and humans, using the rat as an animal model to explore target organs of toxicity for a new drug that significantly enhances thyroid hormone metabolism/clearance and increases TSH levels would not be adequate. In this case, a compromised and dysfunctional hypothalamo-pituitary-thyroid system would confound the toxicity profile explored in preclinical toxicity testing and render the model an inadequate risk predictor for the new drug in humans. Under such conditions, IND and NDA sponsors of drugs exhibiting this activity profile should be encouraged to use alternative animal species for toxicity exploration to provide a more meaningful human risk prediction.

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Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

Cited by 2 publications

References 26 publications

Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels

Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels

Preclinical Development of New Drugs that Enhance Thyroid Hormone Metabolism and Clearance: Inadequacy of Using Rats as an Animal Model for Predicting Human Risks in an IND and NDA

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