Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of fluvastatin, an inhibitor of HMG-COA reductase, in mouse, rat, dog, and monkey

The physiological disposition of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, has been studied in the mouse, rat, dog, and monkey using 14C- or 3H-labeled drug. Oral doses of fluvastatin were absorbed at a moderate to rapid rate. The extent of absorption was dose-independent and was essentially complete in all four species studied. However, the drug was subject to extensive presystemic hepatic extraction followed by direct excretion via the bile, thus minimizing the systemic burden and yielding high liver/peripheral tissue concentration gradients for fluvastatin and its metabolites. Only at high doses far exceeding the intended human daily dose of ca 0.6 mg kg-1 did fluvastatin bioavailability approach unity, apparently due to saturation of the first-pass effect. Dose-normalized blood levels of fluvastatin and total radioactivity were higher in the dog than in the other species, suggesting a smaller distribution volume in the former. Fluvastatin was partially metabolized before excretion, the extent of metabolism being smallest in the dog and greatest in the mouse. The half-life of intact fluvastatin ranged from 1-2h in the monkey to 4-7h in the dog. Regardless of the dose or dose route, the administered radioactivity was recovered predominantly in feces, with the renal route accounting for less than 8 per cent of the dose. No tissue retention of radioactivity was observed, and material balance was essentially achieved within 96h after dosing.     

No evidence for the involvement of the multidrug resistance-associated protein and/or the monocarboxylic acid transporter in the intestinal transport of fluvastatin in rats

Fluvastatin, an amphiphilic anion, shows a nonlinear increase in effective intestinal permeability (P_eff) with increasing lumenal concentrations in rats. The main objective of this study was to investigate whether or not this observation could be attributed to an efflux-mediated transport by the multidrug resistance-associated protein (MRP). In parallel, we investigated the possible involvement of the monocarboxylic acid transporter (MCT) in the rapid intestinal absorption of fluvastatin. Single-pass perfusions were performed in the ileum and colon of the rat, with and without the presence of well-established inhibitors/substrates for the MRP (probenecid) and the MCT (nicotinic acid). The results suggest that neither the MRP nor the MCT are involved to any significant extent in the absorption process of fluvastatin in the rat intestine. Thus, the previously reported concentration-dependent P_eff of fluvastatin in these intestinal regions of the rat is probably not attributable to saturation of any efflux mediated by MRP.     

Fluvastatin decreases cardiac fibrosis possibly through regulation of TGF-beta(1)/Smad 7 expression in the spontaneously hypertensive rats

Statins ameliorate myocardial fibrosis after myocardial infarction. We designed this study to determine whether fluvastatin reduced hypertension-induced myocardial hypertrophy and fibrosis and whether these fluvastatin effects involved transforming growth factor beta1 (TGF-beta1) and Smad 7, factors known to play a role in the myocardial hypertrophy and fibrosis. We randomized 14 week old spontaneously hypertensive rats (SHRs) to receiving vehicle or 5-20 mg/kg/day fluvastatin for 8 weeks. Wistar Kyoto (WKY) rats receiving vehicle or 10 mg/kg/day fluvastatin were also studied. SHRs had an increased blood pressure, left ventricular hypertrophy and fibrosis compared with WKY rats. SHRs also had an elevated TGF-beta1 expression and a decreased Smad 7 expression. These changes in SHRs were dose-dependently attenuated by fluvastatin. For example, the hydroxyproline content was 3.2+/-0.1, 4.0+/-0.1 and 3.5+/-0.1 microg/mg heart and the Smad 7 protein expression was 5.1+/-0.6, 1.0+/-0.1 and 4.1+/-0.7 arbitrary units for WKY rats, SHRs and SHRs receiving 20 mg/kg/day fluvastatin, respectively. The hydroxyproline content in the SHRs treated with or without fluvastatin was positively correlated with the left ventricular mass index, systolic blood pressure and the amount of TGF-beta1 proteins and negatively correlated with the Smad 7 expression level. The left ventricular mass index was positively correlated with the systolic blood pressure. Fluvastatin did not alter the blood pressure, left ventricular mass index and collagen content of WKY rats. These results suggest that fluvastatin reduces hypertension-induced myocardial hypertrophy and fibrosis. These effects may involve an increased expression of Smad 7 and a decreased expression of TFG-beta1. Our results call for clinical studies to evaluate these fluvastatin effects in hypertensive patients.     

Concentration- and Region-dependent Intestinal Permeability of Fluvastatin in the Rat

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intestine in the rat. In-situ single-pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (P_eff) of fluvastatin, antipyrine and D-glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 μM). The effect of lovastatin acid on the bi-directional transport of fluvastatin across the ileal mucosa was also studied. The P_eff of fluvastatin was found to be dependent both on the intestinal region and on the concentration in the intestinal lumen (P < 0.001). Fluvastatin had the lowest P_eff (0.55±0.10 times 10^?4 cm s^?1) in the jejunum at 1.6 μM, and the highest P_eff (1.0±0.16 times 10^?4 cm s^?1) in the colon at 160 μM. The highest concentration of fluvastatin increased the average absorption of water from the intestine by 209% (P < 0.05), and the average P_eff of D-glucose by 29% (P < 0.05). The presence of excess lovastatin acid (100 μM, compared with fluvastatin 1.6 μM) at the luminal side increased the average absorption of water by 218% (P < 0.001), and the P_eff of fluvastatin in the ileum and the colon by 44 and 50%, respectively (P < 0.05). The presence of lovastatin acid on the luminal side in the ileum also increased the blood-to-lumen transport (exsorption) of fluvastatin by 43% (P < 0.001). The increased intestinal absorption of fluvastatin at higher concentrations does not suggest that substantial absorption occurs by any carrier-mediated process in the absorptive direction. The increased bi-directional transport when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent increase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.     

Differential effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on plasma paraoxonase 1 activity in the rat

Statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors), apart from lowering plasma cholesterol, modulate other processes involved in atherogenesis. The aim of this study was to investigate the effect of a natural statin, pravastatin, and of the synthetic one, fluvastatin, on plasma paraoxonase 1 (PON1), the antioxidant enzyme contained in plasma high-density lipoproteins. The adult male Wistar rats received either pravastatin (4 or 40 mg/kg/day) or fluvastatin (2 or 20 mg/kg/day) for 3 weeks. Then, plasma PON1 activity, lipid peroxidation products and total antioxidant capacity were assayed. Fluvastatin at a dose of 20 mg/kg/day decreased paraoxonhydrolyzing activity of PON1 by 23.6% and its phenyl acetate-hydrolyzing activity by 17.4%. Lower dose of this drug as well as either dose of pravastatin had no effect on these activities. Fluvastatin at doses of 2 and 20 mg/kg/day decreased gamma-decanolactone-hydrolyzing activity of plasma by 19.1% and 30.9%, respectively. Statins had no effect on either total or HDL-cholesterol but markedly reduced plasma triglycerides. Fluvastatin had a more marked antioxidant activity, as evidenced by significant reduction of plasma concentration of malonyldialdehyde + hydroxydialkenals and lipid hydroperoxides, as well as by elevation of total plasma antioxidant capacity and plasma concentration of reduced sulfhydryl groups. These results suggest that fluvastatin but not pravastatin decreases plasma PON1 activity in normolipidemic rats, however, the former drug is more effective in reducing the level of oxidative stress.     

Clinical pharmacokinetics of fluvastatin

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.     

Chronic treatment with fluvastatin improves smooth muscle dilatory function in genetically determined hyperlipoproteinemia

We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL: 57 +/- 12 versus WHHL+ fluvastatin: 150 +/- 22%; P < 0.05) and in tendency endothelium-dependent relaxation (WHHL: 26 +/- 5 versus WHHL+ fluvastatin: 83 +/- 29%; (P = 0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL: 480 (13-3821) versus WHHL+ fluvastatin: 808 (467-1595) nmol; P < 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.     

Effect of 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins) on tissue paraoxonase 1 and plasma platelet activating factor acetylhydrolase activities

The authors investigated the effect of pravastatin and fluvastatin on paraoxonase 1 (PON1) activity in plasma, liver, heart, and kidney, as well as on plasma platelet activating factor acetylhydrolase (PAF-AH) in the rat. The animals received pravastatin at doses of 4 and 40 mg/kg/d or fluvastatin at doses of 2 or 20 mg/kg/d for 3 weeks. Fluvastatin (20 mg/kg/d) reduced plasma PON1 activity toward paraoxon and phenyl acetate by 23.6% and 17.4%, respectively. The lower dose of this drug as well as both doses of pravastatin had no effect on plasma PON1. PON1 activity toward paraoxon in the liver of rats treated with 20 mg/kg/d fluvastatin was 27.5% lower than in the control group, and the activity toward phenyl acetate was reduced by 25.4% and 35.9% in rats receiving 2 and 20 mg/kg/d of this drug, respectively. Fluvastatin at 2 and 20 mg/kg/d also decreased cardiac PON1 by 31.3% and 27.3%, respectively. Both statins reduced PON1 activity in the renal cortex and medulla. Statins had no effect on plasma PAF-AH. It is concluded that fluvastatin reduces PON1 activity more efficiently than does pravastatin. Reducing effect on PON1 may negatively modulate atheroprotective potential of statins and may contribute to differences in antiatherosclerotic properties of different drugs in this group.     

Fluvastatin stabilizes the blood-brain barrier in vitro by nitric oxide-dependent dephosphorylation of myosin light chains

Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme-A reductase and the downstream mevalonate pathway is in part responsible for the beneficial effects that statins exert on the cardiovascular system. In this study we aimed at analysing the stabilizing effects of fluvastatin on the blood-brain barrier (BBB) integrity, using an in vitro co-culture model of ECV304 and C6, or primary bovine endothelial cells and rat astrocytes. Fluvastatin dose-dependently (1-25 micromol/l) increased barrier integrity as analysed by measurements of transendothelial electrical resistance (TEER). This effect (117.4+/-2.6% at 25 micromol/l) was significantly reduced by the nitric oxide (NO) synthase inhibitor L-NMMA (300 micromol/l; P<0.01, n=4). The fluvastatin-induced increase of intracellular NO, as analysed by confocal DAF-fluorescence imaging, and the increase in TEER values were significantly reduced in the presence of the isoprenoid geranylgeranyl pyrophosphate (GGPP; 10 micromol/l), whereas farnesyl pyrophosphate had no effect. Immunofluorescent detection of phosphorylated myosin light chains (MLC) revealed a fluvastatin-induced (25 micromol/l) significant reduction of MLC phosphorylation (85.4+/-2.7% control, P<0.001, n=20). This effect was absent if the MLC phosphatase was blocked by calyculin (10 nmol/l). In conclusion, our data demonstrate a BBB stabilizing effect of fluvastatin that correlates with the NO-dependent dephosphorylation of endothelial MLC via the MLC phosphatase.     

Effects of Fluvastatin on the Pharmacokinetics of Repaglinide: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Fluvastatin

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC₅₀) of 4.1 µM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC_0-∞ of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.     

Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate

Hyperbilirubinemia is a frequent side effect induced by long-term therapy with the antibiotic fusidate. The aim of this study was to elucidate the molecular mechanisms of fusidate-induced hyperbilirubinemia by investigating its influence on hepatic transport systems in the canalicular membrane. Using canalicular membrane vesicles from rat liver, we determined the effect of fusidate on the adenosine 5'-triphosphate (ATP)-dependent transport of substrates of the apical conjugate export pump, multi-drug resistance protein 2 (Mrp2, symbol Abcc2) and the bile salt export pump (Bsep, symbol Abcb11). Fusidate inhibited the ATP-dependent transport of the Mrp2 substrates 17beta-glucuronosyl estradiol and leukotriene C4, and the transport of cholyltaurine by Bsep with Ki values of 2.2+/-0.3, 7.6+/-1.3, and 5.5+/-0.8 microM, respectively. To elucidate the in vivo implication of these findings, the effect of fusidate treatment on the elimination of intravenously administered tracer doses of 17beta-glucuronosyl estradiol and cholyltaurine into bile was studied in rats. Treatment with fusidate (100 micromol/kg body weight) reduced the biliary excretion rate of 17beta-glucuronosyl [3H]estradiol and [3H]cholyltaurine by 75 and 80%, respectively. Extended treatment of rats with fusidate (100 micromol/kg body weight, three times daily i.p. for 3 days) reduced hepatic Mrp2 protein levels by 61% (P<0.001). Our data suggest that there are at least two different mechanisms involved in the impairment of transport processes and hepatobiliary elimination by fusidate, direct inhibition of transport of Mrp2 and Bsep substrates by competitive interaction and impairment by a decreased level of hepatic Mrp2.     

Statins prevent oxidized low-density lipoprotein- and lysophosphatidylcholine-induced proliferation of human endothelial cells

The proliferation of endothelial cells is induced by oxidized low-density lipoprotein (oxLDL) and its major component, lysophosphatidylcholine (LPC). The aim of this study was to investigate the effect of statins on the proliferation of endothelial cells derived from human umbilical cord veins (HUVEC). Cerivastatin, simvastatin and fluvastatin caused a dose-dependent inhibition of endothelial cell growth (n=12; P<.01) when using cell counts and [3H]-thymidine incorporation, respectively. The strongest inhibition of HUVEC proliferation was achieved at statin concentrations of 0.1 micromol/l (cerivastatin), 2.5 micromol/l (simvastatin) and 1 micromol/l (fluvastatin). Cell counts were significantly reduced from 22937+/-280.6 (control) to 7791+/-133.6 (cerivastatin), 7292+/-146.6 (simvastatin) and 6792+/-135.5 (fluvastatin) (n=12; P<.01). Interestingly, cell proliferation induced by oxLDL (10 microg/ml) and LPC (20 micromol/l) could be effectively prevented using statins at concentrations between 0.01 and 0.1 micromol/l (cerivastatin), 1 and 2.5 micromol/l (simvastatin) and 0.25 and 1 micromol/l (fluvastatin). This effect of the statins was abolished by preincubation with mevalonate (500 micromol/l). Our results demonstrate an interesting direct effect of statins on the proliferation of human endothelial cells induced by oxLDL and LPC, which may be beneficial to prevent vascular effects of these atherogenic lipids.     

Fluvastatin, an HMG-CoA reductase inhibitor, protects LDL from oxidative modification in hypercholesterolemic rabbits

The antioxidative effect of fluvastatin sodium (fluvastatin) on low-density lipoprotein (LDL) was evaluated in vivo and in vitro. Since ex vivo measurement of the LDL oxidizability is reported to reflect the response of the atherosclerotic process, LDL isolated from rabbits fed a high cholesterol diet for 4 weeks with or without fluvastatin, pravastatin or alpha-tocopherol administration was oxidized by copper ions to estimate conjugated diene formation. Fluvastatin but not pravastatin significantly prolonged the lag time of LDL oxidized by copper ions ex vivo without affecting plasma cholesterol levels at a dose of 3 mg/kg after four weeks of treatment. Alpha-tocopherol-treated rabbits showed dramatically elongated LDL oxidation lag time at a dose of 150 mg/kg. In order to assess the mechanism, the content of alpha-tocopherol, a major endogenous antioxidant in LDL was measured, and we found that only LDL isolated from alpha-tocopherol-treated rabbits contained a significantly larger amount of alpha-tocopherol than that from high cholesterol control rabbits. To elucidate the mechanism further, the effect of fluvastatin on conjugated diene formation during copper-induced LDL oxidation in vitro was studied. Fluvastatin not only prolonged lag time, but also suppressed the rate of LDL oxidation, both in a dose dependent manner above 1 microM, while pravastatin showed no effect. These results suggest the direct antioxidative effect of fluvastatin on LDL oxidation in vivo. Since oxidation of LDL is an important step in the initiation and progression of atherosclerosis, fluvastatin may reduce the risk of this condition not only by lowering plasma cholesterol but also by protecting LDL from oxidation.     

Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days).     

Fluvastatin: a review of its use in lipid disorders

Fluvastatin is an HMG-CoA reductase inhibitor used to treat patients with hypercholesterolaemia. Since fluvastatin was last reviewed in Drugs, trials have shown its efficacy in the secondary prevention of coronary heart disease (CHD) events and death and have expanded knowledge of its effects in primary CHD prevention and its mechanisms of activity. In addition to reducing total (TC) and low density lipoprotein (LDL-C) cholesterol, fluvastatin has antiatherogenic, antithrombotic and antioxidant effects, can improve vascular function, and may have immunomodulatory effects. Although fluvastatin interacts with bile acid sequestrants (requiring separation of doses), its pharmacokinetics permit oral administration to most patient groups. Fluvastatin is well tolerated, with adverse effects usually mild and transient. Use of fluvastatin to reduce lipids in patients with primary hypercholesterolaemia is well established. Its effects are similar in most patient groups, with 20 to 80 mg/day reducing LDL-C by 22 to 36%, triglycerides (TG) by 12 to 18% and apolipoprotein B by 19 to 28% and increasing high density lipoprotein cholesterol by 3.3 to 5.6%. Attempts to find fluvastatin dosages with efficacy equivalent to that of other HMG-CoA reductase inhibitors produce variable results, but larger per-milligram fluvastatin dosages are needed when patients switch from other HMG-CoA reductase inhibitors. Combinations of fluvastatin with fibric acid derivatives and bile acid sequestrants produce additive effects. Small noncomparative studies suggest fluvastatin reduces LDL-C in patients with hypercholesterolaemia secondary to kidney disorders by < or = 40.5% and with type 2 diabetes mellitus by < or = 32%. Three large randomised, double-blind trials show fluvastatin can help prevent CHD events or death and slow disease progression in patients with CHD with or without hypercholesterolaemia. In the Fluvastatin Angiographic Restenosis trial in patients undergoing balloon angioplasty, fluvastatin 80 mg/day for 40 weeks reduced the postangioplasty rate of deaths plus myocardial infarctions (1.5% vs 4% with placebo, p < 0.025) without altering vessel luminal diameters. In the Lipoprotein and Coronary Atherosclerosis Study in patients with coronary artery stenosis, luminal diameter reduced to a significantly lesser extent after fluvastatin 20 mg twice daily than placebo after 2.5 years (-0.028 vs -0.01 mm, p < 0.005). The Lescol in Symptomatic Angina study found reductions in all cardiac events or cardiac death in patients after 1 year of fluvastatin 40 mg/day (1.6% vs 5.6% for placebo, p < 0.05). CONCLUSIONS: An evolving pattern of data suggests that, in addition to its well established efficacy and cost effectiveness in reducing hypercholesterolaemia, fluvastatin may now also be considered for use in the secondary prevention of CHD.     

Diethyl ether fraction of Labrasol having a stronger absorption enhancing effect on gentamicin than Labrasol itself

In our previous study, we had reported that Labrasol has a good gastrointestinal (GI) absorption enhancing effect on poorly absorbable drugs. In order to improve further absorption enhancing effect of Labrasol on gentamicin (GM), which is a representative water-soluble, poorly absorbable drug, Labrasol was fractionated with hexane, diethyl ether, ethyl acetate and water. The absorption enhancing effect of each fraction of Labrasol and Labrasol alone were evaluated in vivo using rats. Each test formulation of GM was administered into the rat colon at a dose of 5.0 mg/kg and plasma GM concentrations were measured by a HPLC method. Among the four fractions of Labrasol and Labrasol, diethyl ether fraction showed the strongest absorption enhancing effect on GM. When the doses of diethyl ether fraction were 1.0, 0.5 and 0.1 ml/kg, the Cmax values were 8.95 +/- 1.46, 8.02 +/- 2.14 and 7.41 +/- 1.25 microg/ml, respectively. Moreover, AUC(0-6) values were also maintained at high level, i.e. 27.28 +/- 5.90, 20.32 +/- 3.79 and 19.61 +/- 2.09 microg h/ml. Based on the AUC(0-6) values obtained with each fraction, the rank order of absorption enhancing effect on GM was diethyl ether > ethyl acetate=hexane > aqueous fraction.     

Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia

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.     

Fluvastatin suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition

Fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts an inhibitory effect on intimal thickening after mechanical injury in normocholesterolemic rabbit artery at a dose not enough to elicit a known action of lipid lowering. This study was designed to determine whether atherosclerotic progression triggered by hypercholesterolemia can be inhibited by fluvastatin under conditions without its hypocholesterolemic effect. Rabbits were fed a 0.5% cholesterol diet or normal diet for 17 weeks and were treated with either fluvastatin (0.3-2 mg/kg/day, p.o.) or pravastatin (2 mg/kg/day, p.o.). Atherogenic features manifested in the cholesterol-diet group, compared with the normal-diet group; they were the increase in serum lipid peroxide level, in the intraluminal lesion area of the aorta, and in macrophage content of the aortic cross-sectional lesion area; the attenuation of endothelium-dependent relaxing response to acetylcholine in the femoral artery; and the increase in serum lipid level. Treatment with fluvastatin, but not pravastatin, inhibited the manifestation of the atherogenic features without a serum lipid-lowering effect. Thus fluvastatin is likely to reduce the risk of atherosclerotic progression, to which endothelial dysfunction, lipid peroxidation, and macrophage accumulation in the vasculature may contribute, irrespective of changes in serum lipid levels.     

Systemic lanthanum is excreted in the bile of rats

Lanthanum carbonate is a non-calcium-based oral phosphate binder for the control of hyperphosphataemia in patients with chronic kidney disease Stage 5. As part of its pre-clinical safety evaluation, studies were conducted in rats to determine the extent of absorption and routes of excretion. Following oral gavage of a single 1500 mg/kg dose, the peak plasma lanthanum concentration was 1.04+/-0.31 ng/mL, 8 h post-dose. Lanthanum was almost completely bound to plasma proteins (>99.7%). Within 24h of administration of a single oral dose, 97.8+/-2.84% of the lanthanum was recovered in the faeces of rats. Comparing plasma exposure after oral and intravenous administration of lanthanum yielded an absolute oral bioavailability of 0.0007%. Following intravenous administration of lanthanum chloride (0.3 mg/kg), 74.1+/-5.82% of the dose (96.9+/-0.50% of recovered lanthanum) was excreted in faeces in 42 days, and in bile-duct cannulated rats, 10.0+/-2.46% of the dose (85.6+/-2.97% of recovered lanthanum) was excreted in bile in 5 days. Renal excretion was negligible, with <2% of the intravenous dose recovered in urine. These studies demonstrate that lanthanum undergoes extremely low intestinal absorption and that absorbed drug is predominantly excreted in the bile.