Effect of itraconazole on cerivastatin pharmacokinetics

Objective: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: A randomized, double-blind, cross-over study design with two phases, which were separated by a wash-out period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. Results: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC_0–∞) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (C_max) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC_0–24 h 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t_1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC_0–24 h of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC_0–24 h of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC_0–24 h and t_1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. Conclusions: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors. Received: 28 June 1998 / Accepted in revised form: 10 October 1998     

Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin

Objective: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydro‐xylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. Methods: Twelve healthy young male subjects received single oral doses of 300 μg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. Results: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (C_max) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (t_max) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective C_max results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). Conclusions: Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 μg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin. Received: 13 August 1997 / Accepted in revised form: 4 October 1997     

Influence of age,renal and liver impairment on the pharmacokinetics of risperidone in man

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CL_oral of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t_1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.     

他汀类药物对于阿尔茨海默病的疗效

流行病学和药理学研究结果显示，胆固醇在阿尔茨海默病(Alzheimer’s disease．AD)的发生中起着重要作用，他汀类药物对于AD具有潜在的治疗作用，今后这类药物可能被用来治疗AD。本综述了目前他汀类药物对AD的研究报道，并对他汀类药物、胆固醇、AD之间的作用机制进行了探讨，为AD的治疗和他汀类药物的新应用提供参考。     

The effect of renal function on the pharmacokinetics of ranitidine

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied.Renal function was assessed in each patient by ⁵¹Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC.Patient groups with renal impairment had significantly increased AUC and t_1/2 with corresponding decreases in CL_p and _z when compared with normal subjects. There was also a significant increase in t_max but not in C_max. There was a high linear correlation between the degree of renal impairment and ranitidine clearance.In patients with GFR 20 ml min^–1, the AUC mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min^–1, the average AUC ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR 20 ml min^–1.     

Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells

Statins are the most widely used drugs for the treatment of hypercholesterolemia. In spite of their overall favorable safety profile, they do possess serious myotoxic potential, whose molecular origin has remained equivocal. Here, we demonstrate in cultivated myoblasts and skeletal muscle cells that cerivastatin at nanomolar concentrations interferes with selenoprotein synthesis and evokes a heightened vulnerability of the cells toward oxidative stressors. A correspondingly increased vulnerability was found with atorvastatin, albeit at higher concentrations than with cerivastatin. In selenium-saturated cells, cerivastatin caused a largely indiscriminate suppression of selenoprotein biosynthesis and reduced the steady state-levels of glutathione peroxidase 1 (GPx1) and selenoprotein N (SelN). Selenite, ebselen, and ubiquinone were unable to prevent the devitalizing effect of statin treatment, despite the fact that the cellular baseline resistance against tert-butyl hydroperoxide was significantly increased by picomolar sodium selenite. Mevalonic acid, in contrast, entirely prevented the statin-induced decrease in peroxide resistance. These results indicate that muscle cells may be particularly susceptible to a statin-induced suppression of essential antioxidant selenoproteins, which provides an explanation for the disposition of these drugs to evoke adverse muscular side-effects.     

Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

The 223A>G polymorphism of the leptin receptor gene and lipid-lowering efficacy of simvastatin in Chinese patients with coronary heart disease

Objective  To investigate whether leptin receptor (LEPR) 223A>G polymorphism influences serum lipid levels and whether this polymorphism affects the effectiveness of simvastatin in Chinese patients with coronary heart disease (CHD). Methods  A total of 312 patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids were determined before and after 12 weeks of treatment. Results  Patients with AA genotype had significantly higher total cholesterol (TC) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than those with GG genotype (P < 0.05) before simvastatin treatment. In addition, the ability of simvastatin to increase HDL-C levels was significantly lower in patients with AA genotype than those with GG genotype (P < 0.05). Conclusions  The 223A>G polymorphism of LEPR significantly modulates the HDL-C response to simvastatin in Chinese patients with CHD. Yan-Ming Sun and Jia Li contributed equally to this study.     

氟伐他汀对心肌梗死后心衰大鼠白介素-1β表达的影响

目的探讨羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂氟伐他汀对急性心肌梗死后心衰大鼠白介素-1β(IL-1β)表达变化的影响。方法♀SD大鼠急性心肌梗死(AMI)术后6 h随机分为:①AMI对照组;②氟伐他汀组;另设:③假手术组。直接灌胃给药8 wk后行高频多普勒超声、血流动力学、心室重塑指标、左室心肌IL-1βmRNA表达的测定。结果与假手术组相比,AMI组左室舒张末期内径(LVEDD)、左室舒张末期容积(LVEDV)、E峰、E峰减速度、E/A、左室舒张末压(LVEDP)、左、右心室心肌肥厚指数、非梗死区胶原容积分数(CVF)和IL-1βmRNA均增加(P均<0.01),左室短轴速短率(FS)和射血分数(EF)均降低(P均<0.01)。与AMI组相比,氟伐他汀组的LVEDD、LVEDV、E峰、E峰减速度、E/A、LVEDP和左、右心室心肌肥厚指数、CVF和IL-1βmRNA均降低(P均<0.01),FS和EF升高(P均<0.01)。结论氟伐他汀能有效抑制心室重塑,延缓心衰进展,其机制可能部分通过下调心梗后心衰大鼠心肌IL-1β的表达,改善炎症反应。     

Synthesis and biological activity of 4,5-polymethylenepyrazole-derived HMG-COA reductase inhibitors

New HMG-CoA reductase inhibitors, in which 3-substituted 4,5-polymethylenepyrazoles are employed as a hydrophobic anchor connected to tetrahydro-4-hydroxy-2H-pyran-2-one by a two-carbon bridge, were designed and synthesized to exhibit significant inhibitory activity comparable to mevinolin. The most potent enzyme inhibitor (11cc, IC₅₀=0.01 μM) is 4-fold more potent than lovastatin.     

HMG-CoA还原酶抑制剂的合成(下)

2芳杂环与侧链的缩合反应 2.1卤代甲基芳香化合物与含醛基6碳侧链的缩合Wittig反应或Wittig-Hornor反应是合成HMG-CoA还原酶抑制剂类药物的常用方法.     

Statins and the risk of idiopathic venous thromboembolism

AIMS: To evaluate the association between current statin use and the risk of idiopathic venous thromboembolism (VTE). METHODS: A population-based retrospective follow-up with a nested case-control analysis using the General Practice Research Database. RESULTS: There were 72 cases of idiopathic VTE. Using normolipidaemic nonuse as the reference group, the adjusted relative risks for idiopathic VTE for current/recent statin use, past statin use, past other lipid-lowering drug use, and hyperlipidaemic nonuse were 0.8 (0.3, 2.7), 2.4 (0.6, 10.0), 1.8 (0.4, 7.4), and 0.9 (0.4, 2.0) in the follow-up analysis, and were 1.1 (0.3, 4.3), 3.7 (0.6, 24.1), 2.0 (0.3, 11.6), and 0.4 (0.2, 1.2) in the case-control analysis. CONCLUSIONS: Current statin use was not associated with a reduced risk of idiopathic VTE.     

The Interconversion Kinetics,Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor,CI-981

The pH dependence of the interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981 ([R-(R*,R*)]-2-(4-fluorophenyl)-,-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-hepatonic acid), are important considerations when chosing and developing one of the forms of these compounds. Over a pH range of 2.1 to 6.0 and at 30°C, the apparent solubility of the sodium salt of CI-981 (i.e., the hydroxyacid form) increases about 60-fold, from 20.4 µg/mL to 1.23 mg/mL, and the profile yields a pK _a for the terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3 to 7.7 and also at 30°C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (±0.53) µg/mL. The kinetics of interconversion and the equilibrium between the hydroxyacid and the lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength (0.5 M) using a stability-indicating HPLC assay. The acid-catalyzed reaction is reversible, whereas the base-catalyzed reaction can be treated as an irreversible reaction. More specifically, at pH <6, an equilibrium favoring the hydroxyacid form is established, whereas at pH >6, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid form. The rate constant for lactone formation, k ₁ is well described by specific acid-catalyzed and spontaneous lactonization pathways, whereas the rate constant for lactone hydrolysis (or hydroxyacid formation), k ₂, is well described by specific acid-, water-, and specific base-catalyzed pathways.     

Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml^–1 · mol^–1; R-PPFG: 576 vs. 304 nmol · ml^–1 · mol^–1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml^–1 · mol^–1; R-PPFG: 7340 nmol · ml^–1 · mol^–1). In summary, the disposition of propafenone and of its active metabolite 5-hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.     

Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes

AIMS: Since 2002, there have been five major outcome trials of statins reporting findings from more than 47,000 subjects. As individual trial results differed, we performed a meta-analysis to ascertain the effectiveness and safety of statins overall and in subgroups. The aim of the study was to estimate the effect of statins on major coronary events and strokes, all-cause mortality and noncardiovascular mortality, and in different subgroups. METHODS: PubMed was searched for trials published in English. Randomized placebo-controlled statin trials with an average follow up of at least 3 years and at least 100 major coronary events were included. For each trial, the statin used, number and type of subjects, proportion of women, mean age and follow up, baseline and change in lipid profile, cardiovascular and non-cardiovascular outcomes were recorded. RESULTS: Ten trials involving 79,494 subjects were included in the meta-analysis. Due to heterogeneity, ALLHAT-LLT was excluded from some analyses. Statin therapy reduced major coronary events by 27% (95%CI 23, 30%), stroke by 18% (95%CI 10, 25%) and all-cause mortality by 15% (95%CI 8, 21%). There was a 4% (95%CI -10, 3%) nonsignificant reduction in noncardiovascular mortality. The reduction in major coronary events is independent of gender and presence of hypertension or diabetes. The risk reduction was greater in smokers (P < 0.05). Coronary events were reduced by 23% (95%CI 18, 29%) in pravastatin trials and 29% (95%CI 25, 33%) in five trials using other statins. Pravastatin reduced strokes by 12% (95%CI 1, 21%) whilst other statins reduced strokes by 24% (95%CI 16, 32%) (P = 0.04). CONCLUSIONS: Statins reduce coronary events, strokes and all-cause mortality without increasing noncoronary mortality. The benefits accrue in men and women, hypertensives and normotensives, diabetics and nondiabetics, and particularly in smokers. Pravastatin appears to have less impact on strokes.