Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus

The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG-CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open-label, three-way crossover study, 24 healthy men received three single-dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14-day washout. The pharmacokinetics of all three drugs and total HMG-CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half-lives of the two statins were unaffected by everolimus. Changes in total HMG-CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single-dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG-CoA reductase inhibitors in plasma to a clinically relevant extent.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

Hydroxymethylglutaryl-coenzyme A reductase inhibitors induce apoptosis in human cardiac myocytes in vitro

Recent findings have implicated hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, an established class of drugs for the treatment of hypercholesterolemia, in tissue remodeling in the heart. Statins induce apoptosis in different cell culture systems including rat neonatal cardiomyocytes. We investigated possible effects of different statins in vitro in human adult cardiac myocytes on the expression of proteins thought to be involved in the regulation of apoptosis such as Mcl-1, an inhibitor of apoptosis, Bax, an inducer of apoptosis, as well as on cytoplasmic histone-associated-DNA-fragments. Human adult cardiac myocytes (HACM) were treated with different statins at concentrations from 0.01 to 5 microM for up to 96 h. Whereas the lipophilic statin simvastatin at a concentration of 5 microM downregulated Mcl-1 mRNA by 49%, the hydrophilic pravastatin had no effect. Bax mRNA levels were not affected by neither of the statins. Simvastatin but not pravastatin reduced Mcl-1 protein expression whereas Bax protein was not detectable in HACM as determined by Western blotting. Simvastatin, atorvastatin and fluvastatin induced an up to seven-fold increase in histone-associated-DNA-fragments whereas pravastatin did not. Simvastatin up regulated histone-associated-DNA-fragments dose-dependently, and mevalonate and geranylgeranyl pyrophosphate reversed this effect to control levels. Our results show that lipophilic statins can induce a pro-apoptotic state in human adult cardiac myocytes in vitro. We speculate that, similar to findings in animal models, statins might be involved in the attenuation of cardiac hypertrophy and remodeling in humans by modulating the balance between cell survival and apoptosis.     

Statins rise cytoplasmic calcium level [Ca2+]i in cultured endothelial cells

Recently, we have shown that some HMG-CoA reductase inhibitors (statins) induce immediate pleiotropic effects in vascular endothelium both in vivo and in vitro, to mention only PGI2-mediated thrombolysis in rats and NO-mediated endothelium-dependent vasodilation in guinea pig coronary circulation. Here we look whether immediate endothelial effect of statins is associated with mobilization of intracellular calcium ions [Ca2+]i in cultured bovine aortic endothelial cells (BAEC). We analyzed the effects of various statins (atorvastatin, cerivastatin, simvastatin, lovastatin and pravastatin at concentration of 10-30 microM) on [Ca2+]i in BAEC in comparison to responses induced by bradykinin (Bk) (10 nM), adenosine diphosphate (1 microM), acetylcholine (100 nM), adrenaline (10 microM), serotonin (10 microM) or calcium ionophore A 23187 (0.1 microM) using FURA-2 according to fluorimetric method of Grynkiewicz et al. Basal [Ca2+]i level in BAEC was between 60 and 100 nM. Bk was the most potent to induce [Ca2+]i response. Delta[Ca2+]i induced by Bk was 331.9 +/- 19.49 nM (n = 36). Delta[Ca2+]i induced by statins (30 microM), i.e. atorvastatin, cerivastatin, simvastatin, lovastatin and pravastatin were 66.4 +/- 7.38% (n = 6), 54.8 +/- 10.12% (n = 5), 58.8 +/- 13.9% (n = 8), 27.7 +/- 7.19% (n = 5) and 0% (n = 5) of the response induced by Bk (10 nM), respectively. In summary, all statins tested, except pravastatin, induce immediate increase in [Ca2+]i in endothelium. This pleiotropic activity of statins in endothelium, most likely not related to the inhibition of HMG-CoA reductase, may represent an intracellular correlate for the immediate release of NO and PGI2 by these drugs that was reported by us previously.     

Modulatory effects of atorvastatin on endothelial cell-derived chemokines, cytokines, and angiogenic factors

STUDY OBJECTIVE: To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. DESIGN: In vitro study using a multiplexing method for protein measurement. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy. CONCLUSION: By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.     

Pharmacoeconomic assessment of HMG-CoA reductase inhibitor therapy: an analysis based on the CURVES study

We conducted a post hoc pharmacoeconomic analysis of a multicenter, open-label, randomized, parallel-group, 8-week efficacy-safety comparison of five HMG-CoA reductase inhibitors-atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The 534 patients requiring cholesterol-lowering therapy took the drugs for 8 weeks with 15 different regimens. Low-density lipoprotein (LDL) was measured after 6 weeks of diet (baseline) and after 8 weeks of treatment with a study drug. At dosages of 10, 20, and 40 mg/day, atorvastatin was associated with significantly greater reductions in LDL than equivalent dosages of the other agents. Cost-effectiveness calculated as the annual acquisition cost/percentage LDL reduction was greatest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 40 mg ($24.96). All other dosages were above $25.00/year/percentage LDL reduction. Atorvastatin was the most cost-effective HMG-CoA reductase inhibitor. Fluvastatin 40 mg/day also had a favorable cost:effectiveness ratio but lowered LDL only by 23%.     

Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme A inhibitors in primary cultured human hepatocytes.

The effects of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin on the contents of cytochrome p450 mRNAs were examined in primary cultures of human hepatocytes prepared from three different livers. Treatment of 2- to 3-day-old human hepatocyte cultures with 3 x 10(-5) M lovastatin, simvastatin, fluvastatin, or atorvastatin for 24 h increased the amounts of CYP2B6 and CYP3A mRNA by an average of 3.8- to 9.2-fold and 24- to 36-fold, respectively. In contrast, pravastatin treatment had no effect on the mRNA level of either CYP2B6 or CYP3A, although treatment with pravastatin did produce the expected compensatory increase in HMG-CoA reductase mRNA content, indicating effective inhibition of cholesterol biosynthesis. Although treatment with the active (+), but not the inactive (-), enantiomer of atorvastatin increased the amount of HMG-CoA reductase mRNA, treatment with each enantiomer significantly induced both CYP2B6 and CYP3A mRNA levels. Treatment of primary cultured rat hepatocytes with the atorvastatin enantiomers effectively increased the amount of CYP3A mRNA, but had no effect on CYP2B or CYP4A mRNA levels, in contrast to fluvastatin, which increased both. Findings for p450 proteins by Western blotting were consistent with the mRNA results. These findings indicate that the ability of a drug to inhibit HMG-CoA reductase activity does not predict its ability to produce p450 induction in primary cultured human hepatocytes, and demonstrate that some, but not all, of the effects of these drugs that occur in primary cultured rat hepatocytes are conserved in human hepatocyte cultures.     

HMG-CoA reductase inhibitors and P-glycoprotein modulation

1. Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2. P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. 3. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods. 4. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.     

Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion

Statins (HMG-CoA reductase inhibitors) exhibit beneficial effects on the vasculature independently of their cholesterol-lowering properties. These pleiotropic effects underlie the ability of statins to reduce intimal hyperplasia in saphenous vein (SV) bypass grafts by attenuating smooth muscle cell (SMC) invasion and proliferation. Although all statins can effectively lower cholesterol, the pleiotropic effects of individual statins may well differ. We therefore compared the concentration-dependent effects of 4 lipophilic statins (simvastatin, atorvastatin, fluvastatin, and lovastatin) and 1 hydrophilic statin (pravastatin) on the proliferation and invasion of SMC cultured from SV of 9 different patients undergoing coronary artery bypass grafting (CABG). The lipophilic statins inhibited SV-SMC proliferation over a 4-day period with an order of potency of fluvastatin > atorvastatin > simvastatin > lovastatin (IC50 range = 0.07 to 1.77 microM). Similarly, these statins also inhibited SV-SMC invasion through an artificial basement membrane barrier (fluvastatin > atorvastatin > simvastatin > lovastatin; IC50 range = 0.92 to 26.9 microM). In contrast, the hydrophilic pravastatin had no significant effect on SV-SMC proliferation at concentrations up to 10 microM, nor did it attenuate SV-SMC invasion (up to 30 microM). Our data provide strong evidence that individual statins possess differential pleiotropic effects on SV-SMC function. This may be of clinical relevance in the selection of individual statins for the treatment of CABG patients.     

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors

The present study was designed to investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG-CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC?? values of 48.0, 14.1 and 3.10 μmol/l, respectively. Simvastatin (1-10 μmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. The area under the plasma concentration-time curve (AUC??∞) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin.     

Antioxidative potential of fluvastatin via the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity

We previously reported that fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a strong lipid lowering drug, exerted an anti-atherosclerotic effect at doses insufficient to lower serum lipids in cholesterol fed rabbits. The evidence demonstrated that the superoxide anions from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a critical role in several steps in the development of atherosclerosis. This study was designed to determine the effects of HMG-CoA reductase inhibitors on the production of the superoxide anions of NADPH oxidase in isolated rat peritoneal neutrophils. Fluvastatin (1-10 microM) decreased phorbol 12-myristate 13-acetate (PMA, 10 nM)-dependent reactive oxygen species (ROS) generation in a concentration-dependent manner. It also (10 microM) decreased PMA-dependent O(2) consumption of the rat neutrophils. These effects were reversed by the addition of mevalonate, a metabolite in the HMG-CoA reductase pathway. Treatment with pravastatin did not show any significant changes. Fluvastatin (10 microM) decreased ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. Rats were treated with either fluvastatin (5 mg/kg per day, p.o.) or pravastatin (5 mg/kg per day, p.o.) for 1 week. Treatment with fluvastatin decreased the PMA-dependent ROS generation. The fluvastatin induced effect on the PMA-dependent ROS generation was reversed by the combined administration with 40 mg/kg mevalonate per day. The antioxidative effect of fluvastatin was thought to have caused not only the scavenging action of the radicals but also to have inhibited ROS generation by inhibiting the NADPH oxidase activity. This antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity may be profitable in preventing atherosclerosis.     

Are all HMG-CoA reductase inhibitors protective against ischemic heart disease?

Effects of pravastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin on myocardial contractile dysfunction during reperfusion after brief ischemia were examined in dogs. Pretreatment of the dog with lipophilic HMG-CoA reductase inhibitors for 3 weeks, simvastatin (2 mg/kg/day), atorvastatin (2 mg/kg/day), fluvastatin (4 mg/kg/day), and cerivastatin (40 micrograms/kg/day) worsened recovery of myocardial contraction during reperfusion after brief ischemia in association with reduced myocardial ATP level. A hydrophilic HMG-CoA reductase inhibitor, pravastatin (2 and 4 mg/kg/day), did not affect the recovery of myocardial contractile function and ATP level during reperfusion following ischemia. The lipophilic inhibitors may enter the myocardial cell, inhibit ubiquinone biosynthesis, and depress ATP generation in mitochondria, leading to worsening of the myocardial stunning after reperfusion subsequent to ischemia.     

A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers

Atorvastatin is a common option among the HMG-CoA reductase inhibitors for the treatment of lipid disorders because of its excellent lipid-lowering efficacy and overall safety profile. Although these agents can rarely cause rhabdomyolysis by themselves, macrolides, among other agents, have been demonstrated to increase the likelihood of this via inhibition of CYP metabolism of the lipid agent. This study investigated the potential for azithromycin and clarithromycin to inhibit the metabolism of atorvastatin. Although there was no interaction between azithromycin and atorvastatin, clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised subject exposure (AUC24) by 82% and peak plasma concentrations by 56%. These data suggest that while azithromycin appears to be safe to coadminister with atorvastatin, clarithromycin should be avoided in patients taking this and similarly metabolized HMG-CoA inhibitors.     

Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells.

Angiotensin II activates p21ras, and mediates cardiac hypertrophic growth through the type 1 angiotensin II receptor in cardiac myocytes. An inhibitor of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase has been shown to block the post-translational farnesylation of p21ras and inhibit protein synthesis in several cell types. Primary cultures of neonatal cardiac myocytes were used to determine whether HMG-CoA reductase inhibitors, lovastatin, simvastatin and pravastatin inhibit the angiotensin II-induced hypertrophic growth. Angiotensin II (10(-6) M) significantly increased protein-DNA ratio, RNA-DNA ratio, ratios of protein synthesis and mitogen-activated protein (MAP) kinase activity. Lipid-soluble HMG-CoA reductase inhibitors, lovastatin (10(-6) M) and simvastatin (10(-6) M) partially and significantly inhibited the angiotensin II-induced increases in these parameters, but a water-soluble HMG-CoA reductase inhibitor, pravastatin (10(-6) M) did not. Mevalonate (10(-4) M) overcame the inhibitory effects of lovastatin and simvastatin on angiotensin II-induced increases in these parameters. A selective protein kinase C inhibitor, calphostin C (10(-6) M) partially and significantly prevented angiotensin II-induced increases in these parameters, and treatment with both lovastatin and calphostin C inhibited completely. Angiotensin II increased p21ras activity and membrane association, and lovastatin inhibited them. These studies demonstrate that a lipid-soluble HMG-CoA reductase inhibitor, lovastatin, may prevent angiotensin II-induced cardiac hypertrophy, at least in part, through p21ras/MAP kinase pathway, which is linked to mevalonate metabolism.     

Atorvastatin Calcium: An Addition to HMG-CoA Reductase Inhibitors

Atorvastatin calcium is an HMG-coenzyme A (CoA) reductase inhibitor that was approved by the Food and Drug Administration on December 17, 1996. Like other such agents, it inhibits the action of HMG-CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein cholesterol. In addition to its effect on lipoprotein profile, atorvastatin reduces triglycerides to a greater extent than other HMG-CoA reductase inhibitors. These actions occur in a dose-dependent fashion. The adverse effect profile is similar to that of other agents in this class. Indications for atorvastatin include primary hypercholesterolemia as well as other lipid disorders.     

The Effect of Pravastatin on Hepatic 3-Hydroxy-3-methylglutaryl CoA Reductase Obtained from Poloxamer 407-Induced Hyperlipidemic Rats

A single 300-mg intraperitoneal injection of poloxamer 407 (P-407) to rats produces a marked hypercholesterolemia for a minimum of 96 hours and increases the activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase compared with the enzyme activity found in microsomal homogenates of control animals. We attempted to determine whether inhibition of microsomal HMG-CoA reductase by pravastatin sodium would yield similar values for the maximum reaction in velocity (V_max) and the HMG-CoA reductase-pravastatin dissociation constant (K_i) when the enzyme was in the activated state compared with the control state. Knowledge of the respective values for V_max and K_i would allow us to determine whether P-407-induced hypercholesterolemia in the rat was refractory to pravastatin treatment. Over a pravastatin concentration range of 0.5–50 nM, enzyme activity in vitro decreased as the drug's concentration increased. A standard Dixon plot of mean values of reciprocal reaction velocity versus pravastatin concentration yielded K_i of 3.7 and 4.1 nM for the control and activated states, respectively. The V_max for conversion of HMG-CoA to mevalonate in vitro in the presence of pravastatin was 3.5-fold greater when assayed in microsomal homogenates obtained from P-407-injected rats compared with control animals. Dixon plot analysis of the data resulted in V_max of 58.1 and 202 pmol•min⁻¹•mg⁻¹ for the control and activated states, respectively. These data suggest that whereas the V_max is affected, injection of P-407 to rats does not alter the binding affinity of pravastatin for receptor(s) contained in HMG-CoA reductase as reflected by similar K_i values. This experimental animal model may be an additional screen with which to rank order the relative potency of HMG-CoA reductase inhibitors by determining the drug's effectiveness when HMG-CoA reductase is in an activated state.     

Comparative tolerability of the HMG-CoA reductase inhibitors.

The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors. Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path. The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole. Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.     

Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes

A number of patients with hyperlipidemia are prescribed 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that are concomitantly used along with the treatment of diabetes mellitus. The effects of atorvastatin and pravastatin on insulin-induced glucose uptake and the related signal transduction in 3T3L1 adipocytes were studied. 3T3L1 fibroblasts were differentiated into adipocytes, pretreated with atorvastatin or pravastatin, and then exposed to insulin. Glucose uptake and the amount of insulin signal proteins were measured. Atorvastatin significantly decreased insulin-stimulated 2-deoxyglucose uptake in 3T3L1 adipocytes associated with the prevention of translocation of GLUT4 into the plasma membrane. The amounts of Rab4 and RhoA that required lipid modification with farnesyl or geranylgeranyl pyrophosphate, in the membrane fraction were decreased by atorvastatin. Insulin-induced tyrosine phosphorylation of IRS-1 and serine/threonine phosphorylation of Akt were reduced by atorvastatin. Pravastatin did not modify these insulin-induced changes in the signal transduction. Inhibitors of the RhoA/Rho kinase system, C3 and Y27632, as well as atorvastatin reduced insulin-induced changes in signal transduction. Atorvastatin and pravastatin did not affect messenger RNA expression, protein level, and tyrosine phosphorylation of insulin receptors. In conclusion, hydrophobic atorvastatin decreases the glucose uptake by 3T3L1 adipocytes since it can enter the cell and prevents lipid modification of some proteins that are involved in the insulin signal transduction process.