Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic pathways of fluvastatin sodium (FV; Lescol, Sandoz compound XU 62-320), [R*,S*-(E)]-(+-)-sodium-3,5-dihydroxy-7-[3- (4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-hept-6-enoate, a potent inhibitor of hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase)--the rate-limiting enzyme in cholesterol biosynthesis--were determined in normal male volunteers at steady state. The metabolite profiles were determined in pooled human blood/plasma, urine, and feces obtained from healthy male volunteers after a single dose of 2 and 10 mg of [3H]FV and at steady state after a single 40 mg daily dose of [3H]FV for 6 sequential days utilizing HPLC coupled with radioactivity monitoring. The two major components in plasma were FV and the desisopropylpropionic acid (4) derivative of FV, the latter a result of oxidative removal of the N-isopropyl group and beta-oxidation of the side chain. Minor amounts of the 4,5-pentenoic acid derivative of FV, the threo-isomer of FV, the trans-lactone of FV, and conjugates of 5-hydroxy FV and 6-hydroxy FV were also present in plasma. Parent FV was not present in feces, the major excretory route, or in urine. In urine, 4 and conjugates of 5-hydroxy FV, and 6-hydroxy FV were present, and each represented < 1% of the dose. In feces 5-hydroxy FV, 6-hydroxy FV, and desisopropyl-FV represented the only peaks of significance. The metabolism of FV leading to the 5-hydroxy FV and 6-hydroxy FV was not stereospecific.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biotransformation of fluvastatin sodium in humans. 810 14

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical implications of the biopharmaceutical properties of fluvastatin. 819 18

Fluvastatin sodium (Lescol) is the first synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor to be studied extensively in humans. Absorption of fluvastatin is complete and unaffected by the presence of food. Systemic exposure is limited because of extensive sequestration by the liver and/or first-pass metabolism, a plasma half-life of approximately 30 min, no circulating active metabolites, and no accumulation of drug during chronic dosing. Approximately 95% of a single dose of fluvastatin is excreted via the biliary route with less than 2% as the parent compound. Studies investigating the effect of food on fluvastatin pharmacokinetics have demonstrated marked reductions in the rate of bioavailability (Cmax) of 40% to 60%. A comparison of drug administration with the evening meal or at bedtime revealed no significant differences in either the extent of bioavailability (area under the curve; AUC) or pharmacodynamic effect [reduction in low-density lipoprotein cholesterol (LDL-C)]. Relative to the general population, plasma fluvastatin concentrations do not vary as a function of either age or gender. Administration of a single 40-mg dose to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both AUC and Cmax. Drug interaction studies with fluvastatin and cholestyramine (CME) demonstrated a lower rate and extent of fluvastatin bioavailability; no impact on efficacy was demonstrated when CME was given 4 h before fluvastatin dosing in clinical trials. Interaction studies with niacin and propranolol demonstrated no effects on fluvastatin plasma levels, and fluvastatin administered to a patient population chronically receiving digoxin had no effect on the AUC of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics of fluvastatin and specific drug interactions. 829 46

Cardiovascular disease remains a significant cause of morbidity and mortality in patients who have undergone renal transplantation, with one of the main risk factors being post-transplantation hyperlipidaemia. To date, however, optimal management of elevated lipid levels in such patients has been hindered by the lack of both effective and safe treatments, coupled with concerns over probable interactions with immunosuppressive therapy, particularly cyclosporin. Numerous studies confirm that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, such as fluvastatin, are effective lipid-lowering agents in renal transplant recipients, supporting findings in other patients' groups. Moreover, based on investigations of metabolic profile and clinical observation, fluvastatin (at dosages of up to 80 mg/day) is well tolerated in renal transplant recipients receiving cyclosporin. In clinical trials to date, no instances of rhabdomyolysis have been observed during co-administration of fluvastatin and cyclosporin. The potential of fluvastatin for improving survival in renal transplant recipients, in terms of both cardiovascular mortality and graft rejection, is currently being investigated in two ongoing studies: ALERT (Assessment of Lescol [fluvastatin] in Renal Transplantation) and SOLAR (Study of Lescol [fluvastatin] in Acute Rejection). The results of these landmark studies should confirm the safe utility of fluvastatin in the renal transplantation setting.
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PMID:Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience. 1065 72

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors (statins) have become a widely prescribed family of lipid lowering agents. Cholesterol synthesis occurs predominantly in liver which is the target organ of statins. We studied the effects of fluvastatin (Lescol), a member of the statin family, on hepatic protein regulation. Male F344 rats treated with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P<0.005). Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase. Treatment also triggered alterations in key enzymes of carbohydrate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeostasis and protease activity. The latter set of protein alterations indicates that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets and that the induction levels of these enzymes may serve as a measure of potency of individual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assay format to compare efficiently and accurately the therapeutic windows of different members of the statin family.
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PMID:Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin. 1132 96

Fluvastatin sodium (Lescol, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor that limits cholesterol biosynthesis, is available as a 40-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. This phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-640 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabilization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, were randomly assigned to four groups to receive oral fluvastatin extended-release (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was observed after single and multiple dosing. At 640 mg, fluvastatin extended-release was not well tolerated. Six of the seven actively treated patients at this dose experienced adverse events, including diarrhea, headache, and clinically relevant elevations in serum transaminase concentrations. In addition, nonlinear pharmacokinetics, possibly due to saturation of first-pass metabolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.
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PMID:Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia. 1133 1