Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Statins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMed2004

Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology.

PURPOSE OF REVIEW: The results of a landmark clinical study comparing intensive statin therapy with conventional statin therapy, in patients with acute coronary syndromes (ACS), are reviewed. The mechanisms behind these results are analysed drawing data from vascular and cell biology. RECENT FINDINGS: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that intensive statin therapy with 80 mg of atorvastatin to achieve a low-density lipoprotein cholesterol of 62 mg/dl resulted in a 3.9% absolute and a 16% relative risk reduction in death or major cardiovascular events up to 2 years, compared to 40 mg of pravastatin, in patients with ACS. The results were especially significant as intensive statin therapy resulted in a very early benefit (<30 days) and occurred against a background of percutaneous coronary intervention (69%) for the index admission and high use of medications for secondary prevention. The PROVE IT and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) C-reactive protein sub-study also showed that atorvastatin (80 mg) resulted in a significant reduction in markers of inflammation, whilst the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that intensive statin therapy was associated with reduced progression of atherosclerosis compared with conventional doses of statins. SUMMARY: Intensive statin therapy results in a significant early reduction in adverse cardiac events in ACS patients which are sustained over 2 years. The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.

Acute Disease↗
PubMed2005

The statins--therapeutic diversity in renal disease?

PURPOSE OF REVIEW: Statins significantly reduce cholesterol synthesis and reduce cardiovascular morbidity and mortality. In addition, they appear to have beneficial effects independent of their ability to lower cholesterol. Recent publications suggesting a potential role for statin therapy in chronic renal insufficiency, hypertension and following organ transplantation are reviewed. RECENT FINDINGS: Pharmacokinetic studies have shown statins to be well-tolerated and effective in patients on long-term haemodialysis, providing equivalent control of lipid levels to that seen in matched controls. Preliminary clinical trials suggest that statins may have beneficial disease-modifying effects in chronic inflammatory disease. Furthermore, immunosuppressive and immunomodulatory actions may confer benefit following cardiac transplantation, but this remains to be demonstrated definitively in renal transplant patients. Data to date suggest that, in addition to reduction of cardiovascular risk, statins may help slow the progress of chronic renal insufficiency, particularly in patients with proteinuria. Addition of statin therapy may also contribute to the control of systemic and pulmonary hypertension. SUMMARY: Encouraging data in support of a wider spectrum of use for statins are emerging. In addition to reduction of cardiovascular risk through lipid lowering, they may represent an important adjunctive therapy in patients with chronic kidney diseases and post-transplantation. However, further large, well-designed clinical trials are required before their widespread use can be recommended in this setting.

Cardiovascular Diseases↗
PubMed2002

Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.

Clinical trials with statins have demonstrated a marked reduction of cardiovascular mortality. However, it remains controversial whether these clinical benefits stem from powerful cholesterol-lowering effects of statins or whether they are due in part to their cholesterol-independent effects on vascular function, plaque growth, plaque rupture, or thrombosis. The identification of several mechanisms through which statins decrease the recruitment of monocytes and T cells into the arterial wall and inhibit T cell activation and proliferation in vitro have prompted speculations that immunomodulatory effects of statins may be beneficial in recipients of organ transplants. Hypercholesterolemia is frequent in these patients, and delayed-type hypersensitivity reactions in the arterial walls of the graft may be compounded by chronic inflammation associated with conventional atherogenesis. To assess the potential clinical relevance of immunomodulatory effects of statins, the role of the immune system in atherogenesis and the effects of statins in vitro in experimental models and in clinical trials will be reviewed. It is concluded that despite solid in vitro evidence, clinical evidence for an independent immunosuppressive effect of statins in organ transplant patients is presently insufficient; however, further investigation of their in vivo occurrence and clinical relevance is warranted.

Animals↗
PubMed2002

Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.

Acute Kidney Injury↗
PubMed2006

Statins: are any questions unanswered?

PURPOSE OF REVIEW: To summarize recent and ongoing randomized trials of statin therapy for the prevention of major vascular events. RECENT FINDINGS: Four large-scale randomized trials have compared high-dose vs. standard doses of statin therapy among patients with coronary heart disease, and their results suggest that higher doses are more effective for preventing major vascular events, albeit with evidence of increased toxicity. There is now clear evidence that statin therapy is effective among most patients with type 2 diabetes, although uncertainty remains about the benefits in those with advanced nephropathy. Ongoing trials will assess whether statin therapy is beneficial among patients with noncoronary vascular disease (such as congestive heart failure, cerebrovascular disease, or aortic stenosis), and among people with comorbid conditions or risk factors that increase the risk of vascular disease (including chronic kidney disease and raised C-reactive protein with below average low-density lipoprotein cholesterol). SUMMARY: Statin therapy safely reduces the risk of vascular events in a wide range of patients. Uncertainties persist about the effects of higher statin doses and the role of statins among patients with specific conditions or risk factors.

Cardiovascular Diseases↗
PubMed2007

Beta-blockers and statins are individually associated with reduced mortality in patients undergoing noncardiac, nonvascular surgery.

BACKGROUND: Patients undergoing noncardiac, nonvascular surgery are at risk for perioperative mortality owing to underlying (a)symptomatic coronary artery disease. We hypothesized that beta-blocker and statin use are associated with reduced perioperative mortality. METHODS: We performed a case-control study in 75 581 patients who underwent 108 593 noncardiac, nonvascular surgery at the Erasmus Medical Center between 1991 and 2001. Cases were the 989 patients who died during hospital stay after surgery. From the remaining patients, 1879 matched controls (age, sex, calendar year and type of surgery) were selected. Information was then obtained regarding the use of beta-blockers and statins and the presence of cardiac risk factors. RESULTS: The median age of the study population was 63 years; 61% were men. beta-blockers were less often used in cases than in controls (6.2 vs. 8.2%; P=0.05), as were statins (2.4 vs. 5.5%; P<0.001). After adjustment for the propensity of beta-blocker use and cardiovascular risk factors, beta-blockers were associated with a 59% mortality reduction (odds ratio 0.41; 95% confidence interval 0.28-0.59). Statins were associated with a 60% mortality reduction (adjusted odds ratio 0.40; 95% confidence interval 0.24-0.68). A significant interaction between beta-blockers and statins was observed (P<0.001). In the presence of each other, statins and beta-blockers were not associated with reduced mortality (adjusted odds ratio 2.0 and 95% confidence interval 0.74-5.7 and adjusted odds ratio 1.3 and 95% confidence interval 0.52-3.2). It should be, however, noted that only nine cases and 29 controls used both agents simultaneously. CONCLUSION: This case-control study provides evidence that beta-blockers and statins are individually associated with a reduction of perioperative mortality in patients undergoing noncardiac, nonvascular surgery.

Adrenergic beta-Antagonists↗
PubMed2006

The safety and efficacy of achieving very low LDL-cholesterol concentrations with high dose statin therapy.

PURPOSE OF REVIEW: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy. This review examines the safety and efficacy of treating to very low LDL-cholesterol. RECENT FINDINGS: Four clinical trials, Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) in stable coronary artery disease and Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 following acute coronary syndromes, have examined intensive statin therapy compared to moderate statin therapy. These trials and a meta-analysis demonstrated that intensive statin therapy reduces cardiovascular events. Subsequent analyses from these trials suggest that very low levels of LDL-cholesterol can be achieved safely and may improve clinical outcomes. A note of caution regarding hemorrhagic events following stroke with intensive statin therapy was raised by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial despite impressive reductions in cardiovascular events. SUMMARY: A growing body of evidence suggests progressive benefit for lowering LDL-cholesterol aggressively with intensive statin therapy in coronary artery disease. Future trials will be needed to define whether there is a level of LDL-cholesterol beyond which further benefit is not seen or safety concerns emerge.

Cholesterol, LDL↗
PubMed2006

The dyslipidemia of chronic renal disease: effects of statin therapy.

PURPOSE OF REVIEW: Dyslipidemia is a prevalent condition in patients with chronic renal disease, but is often left untreated. Statin treatment constitutes an effective way to improve lipid abnormalities. This review summarizes present studies on dyslipidemia and its treatment in patients with chronic renal disease. RECENT FINDINGS: The specific dyslipidemia in renal disease is associated with the presence of proteinuria and decreased creatinine clearance, and may even adversely affect the progression of chronic renal disease. Statin therapy may have renoprotective effects due to a combination of lipid lowering and pleiotropic effects. Statins exert several anti-inflammatory properties and lead to a decrease of proteinuria. Post-hoc analyses of large-scale lipid lowering trials have shown that the reduction of cardiovascular risk was equivalent to the reduction achieved in patients without chronic renal failure. We feel, however, that if intervention with statins is postponed until patients reach end-stage renal disease, statins have limited benefit. SUMMARY: Present studies suggest that patients with renal disease should be screened early for dyslipidemia and that statins have to be considered as the lipid lowering therapy of choice. These drugs reduce cardiovascular risk. Further studies are needed to firmly establish whether statins preserve renal function.

Cardiovascular Diseases↗
PubMed2005

Statin use after acute myocardial infarction: a nationwide study in Denmark.

AIMS: To study outpatient statin use after first acute myocardial infarction (AMI) in Denmark between 1995 and 2002 and to determine the predictors of statin use. METHODS: This is a nationwide population-based study using administrative registries. Patients with first AMI between 1995 and 2002 older than 30 years of age and alive 6 months after discharge (n = 45 219) were identified through the National Patient Registry. The statins purchased by these patients within 6 months after discharge were determined using the Registry of Medicinal Product Statistics, a nationwide prescription database. RESULTS: Statin use following AMI increased from 13% in 1995 to 61% in 2002. In 2002, 81% of patients aged 30-64 years used statins. Older patients used fewer statins, but use increased more among patients aged 75-84 years: from 1.3% to 43%. Use in elderly patients did not differ according to gender in 2000-02, but young men used more than younger women. In 2000-02, patients with diabetes (odds ratio (OR): 0.84; 95% confidence interval (CI): 0.74-0.95) and with heart failure (OR: 0.70; 95% CI: 0.64-0.76) were undertreated; this trend was present throughout the period. CONCLUSIONS: In this nationwide study, younger patients after AMI had high statin use in 2002, but high-risk patients such as those with diabetes and heart failure were still being undertreated.

Adult↗
PubMed2003

Physicians' prescribing attitudes to combined therapy with statins and fibrates.

OBJECTIVE: To assess the impact of a package insert revision and a drug-drug interaction warning embedded in a computerized prescription ordering system, on physicians' prescribing of concomitant statins and fibrates. METHODS: Data were obtained using a computerized prescription order entry system before and after administrative intervention advising of potentially adverse effects of this combined therapy. The number of prescriptions for statins and fibrates were counted monthly from January 1998 to June 2002 at the National Cardiovascular Center (NCVC). Counting was based on information from a prescription database file compiled from a computerized order entry system. The total number of prescriptions and frequency of requests for statins and fibrates were compared with the timing of either package insert revision or introduction of the warning on a computerized prescription ordering system. In addition, laboratory testing of renal function using serum creatinine (Scr) assays in patients treated with combined statins and fibrates was obtained from medical records at two stages during the study period (stage 1, January 1998 to June 1998; stage 2, January 2002 to June 2002). RESULTS: There were 204 prescriptions for concomitant statins and fibrates at the beginning and 50 prescriptions at end of the study period. The number of prescriptions began to decrease in the latter half of 1999 with the percentage of concomitant use of statins and fibrates showing an evident downward trend from January 2001. This acceleration in the downward trend coincided with the introduction of the computerized warning message. Scr levels were measured in 43.8% of patients in stage 1 and in 48.3% of patients in stage 2 in the past month. The percentage of patients having Scr levels measured in the past 6 months was 85.3% in stage 1 and 84.5% in stage 2. There was no significant difference in the percentages of patients whose Scr levels had been measured between the two stages. CONCLUSION: Revision of package inserts concerning combined therapy of statins and fibrates led to physicians' prescribing fewer of these combinations. A warning message displayed on a computerized prescription order entry system accentuated this effect.

Anticholesteremic Agents↗
PubMed2004

The influence of statin characteristics on their safety and tolerability.

The efficacy of the statins for both primary and secondary prevention has now been clearly established in patients across the spectrum of cardiovascular risk. In addition to their primary effect in reducing plasma cholesterol, the statins possess various 'pleiotropic' effects that may contribute to their clinical effectiveness in reducing cardiovascular events, e.g. improvement of endothelial function, reduction of low-density lipoprotein-cholesterol oxidation and stabilisation of atheromatous plaques. Although statins share similar chemical characteristics, they differ significantly in terms of their molecular synthesis, solubility and pharmacokinetic behaviour and metabolism. Side-effects secondary to longterm statin therapy are rare, but rhabdomyolysis may occur when statins are administered together with other drugs that have a direct toxic effect on muscle or which inhibit statin metabolism. Among the various statins, it would appear that fluvastatin has the lowest propensity to interact with other drugs and the least potential to induce myotoxicity.

Cardiovascular Diseases↗
PubMed2006

Effects of various statins on cytokine-dependent growth and IgE-dependent release of histamine in human mast cells.

BACKGROUND: Statins are inhibitors of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in mevalonic acid (MVA)-dependent signaling. Recent data suggest that statins exhibit profound inhibitory effects on growth and function of various immune cells. In the present study, we examined the in vitro effects of five different statins on primary human mast cells (MCs), MC progenitors, and the human MC line HMC-1. METHODS: Histamine release experiments were conducted on isolated MCs using statins and an anti-immunoglobulin E (IgE) antibody. Culture experiments were performed with stem cell factor (SCF) and interleukin (IL)-6, and cord blood-derived progenitors. RESULTS: Preincubation of primary lung MCs with cerivastatin or atorvastatin (1-50 microM) for 24 h resulted in inhibition of anti-IgE-induced release of histamine. The effects of both statins were dose-dependent. Moreover, both statins, and to a lesser degree lovastatin, were found to inhibit the SCF-induced differentiation of MCs from their progenitors. The other statins tested (simvastatin, pravastatin) did not affect mediator release or growth of MCs. CONCLUSIONS: Cerivastatin and atorvastatin act as inhibitors of growth and function of human MCs.

Apoptosis↗
PubMed2006

Statins reduce macrophage inflammatory protein-1alpha expression in human activated monocytes.

1. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exhibit a wide variety of anti-atherogenic effects that may be independent of their property to lower plasma cholesterol. 2. In order to systematically investigate these effects at a cellular level, we investigated gene expression in phorbol myristate acetate (PMA)-activated and non-activated human THP-1 monocytes in response to statins using cDNA arrays. 3. Of 588 genes tested, 26 were differentially expressed in the presence of statins. A marked reduction was found for the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha). The decrease in MIP-1alpha mRNA expression after incubation with statins was confirmed by quantitative reverse transcription-polymerase chain reaction in THP-1 monocytes and human freshly isolated monocytes. Macrophage inflammatory protein-1alpha protein in THP-1 monocytes was reduced from 377 to 299 and 305 pg/mL by 0.1 micro mol/L simvastatin and 0.01 micro mol/L cerivastatin, respectively. The reduction in MIP-1alpha expression by statins was due, at least in part, to transcriptional inhibition of MIP-1alpha promoter activity. 4. The CC receptor ligand MIP-1alpha is a chemokine that has been implicated in atherosclerotic lesion formation. The present findings suggest that statin-mediated immunomodulation by inhibiting MIP-1alpha could contribute to the beneficial effects of statin therapy independent of lowering plasma cholesterol.

Cell Separation↗
PubMed2005

Statins, nitric oxide and neovascularization.

Several landmark clinical trials suggest that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have additional cardiovascular protective activity that may function independently of their ability to lower serum cholesterol. The cardiovascular protective effects of statins are partly caused by the activation of postnatal neovascularization. At therapeutic doses, statins promote proliferation, migration and survival of endothelial cells, induce mobilization and differentiation of bone marrow-derived endothelial progenitor cells by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) and nitric oxide (NO) signal pathway. However, at excessive doses, statins may decrease protein isoprenylation as well as inhibit endothelial cell growth and migration. NO is an important signaling molecule that regulates a wide range of physiological and pathological processes in different tissues. There is substantial evidence that effective neovascularization requires endothelium-derived NO. Statins have pleiotropic effects on the expression and activity of endothelial nitric oxide synthase (eNOS) and lead to improved NO bioavailability. NO plays an important role in the effects of statins on neovascularization. In this review, we focus on the effects of statins on neovascularization and highlight specific novel targets, such as endothelial progenitor cells and NO.

Animals↗
PubMed2006

Statin use is independently associated with smaller infarct volume in nonlacunar MCA territory stroke.

BACKGROUND: Studies have shown an association between HMG-CoA reductase inhibitors (statins) and improved stroke outcomes, possibly secondary to neuroprotective properties. OBJECTIVE: To assess whether patients taking statins prior to ischemic stroke have smaller infarcts on magnetic resonance imaging (MRI), adjusting for other relevant clinical factors. DESIGN: We retrospectively reviewed the Cleveland Clinic Foundation (CCF) Neurology Inpatient Database from June 2002 through June 2004. Demographics, medications, stroke subtype, diffusion-weighted imaging (DWI) infarct volume, admission NIHSS, and hours to MRI were collected. Patients with a nonlacunar middle cerebral artery (MCA) territory infarct and MRI less than 48 hours from symptom onset were included (n= 143). A multivariable linear regression model was constructed to determine independent predictors of smaller infarct volume. RESULTS: A total of 143 patients were studied, including 38 patients taking statins at the time of their stroke. In univariate analysis, patients using statins were significantly more likely to have a history of hyperlipidemia, atrial fibrillation, and coronary artery disease and to be using coumadin, antiplatelet drugs, and angiotensin-converting enzyme inhibitors. Patients on statins had a tendency toward smaller infarcts in univariate analysis (median 25.4 cm(3) vs. 15.5 cm(3), P= 0.054). In multivariable linear regression analysis statin use, patient age, and TIA within the prior 4 weeks were independently associated with smaller DWI volumes; vessel occlusion on vascular imaging, and cardioembolic stroke subtype with larger infarct size. CONCLUSIONS: Statin use prior to the onset of nonlacunar MCA infarction was associated with a smaller infarct volume independent of other factors. Further studies utilizing both clinical and radiologic outcomes will be required to confirm these findings.

Aged↗
PubMed2006

Growth inhibition of Candida species and Aspergillus fumigatus by statins.

Statins are a class of drugs widely used for lowering high cholesterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the synthesis of cholesterol. We studied the effects of two major statins, simvastatin and atorvastatin, on five Candida species and Aspergillus fumigatus. The statins strongly inhibited the growth of all species, except Candida krusei. Supplementation of Candida albicans and A. fumigatus with ergosterol or cholesterol in aerobic culture led to substantial recovery from the inhibition by statins, suggesting specificity of statins for the mevalonate synthesis pathway. Our findings suggest that the statins could have utility as antifungal agents and that fungal colonization could be affected in those on statin therapy.

Antifungal Agents↗
PubMed2004

Statins in solid organ transplantation: is there an immunosuppressive effect?

Cardiac allograft vasculopathy is one of the major causes of mortality late after heart transplantation. This disease process occurs to a lesser extent in patients with other donor organs; however, a long-term graft dysfunction is similarly described in kidney, liver and lung transplant recipients. There are multiple immune and nonimmune risk factors associated with this vasculopathic disease process, one of which includes hyperlipidemia. Use of lipid lowering agents, specifically HMG-CoA reductase inhibitors (statins) was initially reported to have possible immunosuppressive effects in a single center study of heart transplant recipients. This has not been observed in kidney transplant recipients; however, a large randomized trial demonstrated a significant cardiovascular risk reduction in fluvastatin-treated kidney transplant patients, outcome similar to the numerous nontransplant clinical trials of statins in atherosclerosis. In two recent in vitro studies, statins have been reported to repress induction of MHC-II by interferon-gamma and selectively block leukocyte function antigen-1, both of which decrease T-lymphocyte activation. In conclusion, statins appear to have outcome benefits in heart and kidney transplant patients; however, firm evidence for a clinical immunosuppressive effect is lacking. Further studies in humans will be needed to demonstrate this potential effect of statins. Overall, the outcome benefits of statins from the heart and kidney clinical studies provide a firm rationale to support the use of statins in organ transplantation.

Arteriosclerosis↗
PubMed2002

Effects of fibrates on metabolism of statins in human hepatocytes.

This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of beta-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a beta-oxidation product (IC(50) approximately 50 and 15 microM, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC(50) approximately 50-60 microM) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC(50) approximately 30 to 60 microM) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (K(i) = 87 microM) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the beta-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.

Aryl Hydrocarbon Hydroxylases↗