Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)It was reported that CYP2D6 in microsomes derived from lymphoblastoid cells with human cDNA shows strong enzyme activity for the metabolism of R-and S-carvedilol. 8)Poor metabolism through CYP2D6 was found in 7% of Caucasian subjects, and two common defective alleles responsible for the poor metabolism are CYP2D6*4 and *5.9) The gene frequency of individual variants of CYP2D6 shows a marked interethnic difference, and poor metabolism is found in less than 1% of Asian subjects. 9) Among Asian extensive/ intermediate metabolizers, the three most common alleles of the CYP2D6 gene are CYP2D6*1, *2, and *10. The mutant allele of CYP2D6 (CYP2D6*2) does not affect the enzyme activity, whereas the CYP2D6*10 allele causes the low expression and affinity of CYP2D6. 10,11) In the present study, we estimated the pharmacokinetic parameters of R-and S-carvedilol in 23 healthy Japanese volunteers by the Bayesian method using a nonlinear mixed effects model (NONMEM) program. We then examined the effect of the CYP2D6 polymorphisms on the stereoselective pharmacokinetics of carvedilol. MATERIALS AND METHODS Subjects and Study ProtocolsTwenty-three healthy Japanese volunteers (19 men and 4 women) participated in this study. The age was between 22 and 44 years old (mean: 29.1), and the body weight was between 47 and 86 kg (mean: 64.7). They were given 5 mg (two 2.5 mg-tablets: 7 men and 2 women) or 10 mg (one 10 mg-tablet: 12 men and 2 women) of carvedilol (Artist ® tablet; Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan) at least 2 h before a meal, because the peak blood drug concentrations are attained at 0.5-1 h after oral administration following an over night fast.12) Carvedilol was taken with a glass of water, and 5 ml of blood was taken at 2 and 6 h after dosing. All the subjects were physicians or pharmacists, and they chose the dose of carvedilol by themselves. The mean (ϮS.D.) body weight in the subjects taking 5 mg and 10 mg carvedilol was 57.9Ϯ6.7 kg and 69.1Ϯ 9.9 kg, respectively. They all gave written consent to participate in this study, which was approved by the ethics committee of Toyama Medica...
In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.
arly reperfusion of an occluded coronary artery preserves myocardial viability and function by limiting the size of the myocardial infarct. 1,2 However, despite early reperfusion, myocardial ischemia-reperfusion (IR) injuries, including no reflow, stunning and reperfusion arrhythmias, sometimes occur, thereby attenuating the cardioprotective effect of reperfusion therapy. 3 Recent studies in experimental animals have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate IR injury independently of their lipid-lowering action. [4][5][6][7][8] Statins have pleiotropic effects, including improvement of endothelial function by increased nitric oxide (NO) bioavailability, 9 and antioxidant 10 and antiinflammatory actions, 11 which may explain their attenuation of IR injury. The experimental result of cardioprotection by statins has therapeutic implication for patients with acute coronary syndrome who will be treated with reperfusion therapy; however, the time at which statin treatment was administered before IR varied from hours to days, and the Circulation Journal Vol.70, December 2006 results are conflicting. 5,12 It is not clear whether acute administration of statins at the onset of ischemia or reperfusion will prevent or attenuate the IR injury.Oxidative stress plays an important role in IR injury, and antioxidants such as superoxide dismutase and catalase could limit the infarct size in IR. 13 Statins are known to decrease free radical generation in the vascular wall 14,15 and myocardium, 16 which suggests that statins may protect the ischemic myocardium from IR injury via suppression of oxygen-derived free radicals produced upon reperfusion. Among the statins, fluvastatin (FV) has a potent free radical scavenging property derived from its chemical structure 17 and the purpose of the present study was to elucidate the effects of acute administration of FV and the role of its antioxidant property on IR injury in rats. MethodsThe experimental procedures followed the approved guidelines for animal experimentation at the University of Toyama. Myocardial IRMale Wistar rats weighing 270-380 g (n=103) were intubated under ether anesthesia and ventilated using a rodent respirator. The heart was exposed by left thoracotomy and the left coronary artery was ligated 2-3 mm from its origin Background Three-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are known to attenuate myocardial ischemia-reperfusion (IR) injury. Fluvastatin (FV) has a potent free radical scavenging action, but it is unclear whether the timing of FV administration could affect its cardioprotective effect or if the antioxidant property of FV might attenuate IR injury. Methods and Results IR was induced in rats by left coronary artery occlusion for 30 min followed by 24-h reperfusion. The rats were divided into 4 groups: oral FV group (10 mg/kg per day for 2 weeks before ischemia); iv, FV group (10 mg/kg) before ischemia; iv, FV group (10 mg/kg) before reperfusion; and control gr...
t is generally accepted that excess levels of norepinephrine (NE) could lead to myocardial injury. [1][2][3][4] Prolonged myocardial ischemia causes a large amount of NE to be released from the sympathetic nerve terminals via non-exocytotic local metabolic mechanism independently of central sympathetic activation, and this excessive NE may promote myocardial injury. 5 Reperfusion following prolonged ischemia would prevent progression of ischemic cell necrosis, whereas reperfusion itself causes myocardial injury, the phenomenon known as reperfusion injury. [6][7][8][9][10] Increased interstitial concentration of NE during ischemia may be involved in the pathogenesis of reperfusion injury, because NE is a source of free radicals. [11][12][13] Previous studies have shown that auto-oxidation of NE results in the generation of highly reactive ·OH radicals. 12,13 Thus, the pathogenesis of catecholamine-induced myocardial injury in the setting of reperfusion following prolonged ischemia is multifactorial, but the relative role of this NE-derived free radical formation in increasing the size of the infarct after reperfusion remains unclear. Accordingly, we studied the effects of cardiac denervation on free radical formation and infarct size in rats with reperfusion following prolonged ischemia and compared them with those of -adrenoceptor blockade. Methods Experimental AnimalThe experimental procedures were approved by the guidelines for animal experimentation at Toyama Medical and Pharmaceutical University. A total of 48 male Wistar rats weighing 300-350 g were used for induction of myocardial ischemia as described previously. 14 Briefly, the rats were anesthetized with sodium pentobarbital (30 mg/kg, ip), and a left thoracotomy was performed to exteriorize the heart. The left coronary artery was ligated 2-3 mm from its origin with a suture of 5-0 prolene (Ethicon, Inc, Somerville, NJ, USA) for 30 min, and then the ligature was released.The animals were divided into 3 groups: control, phenol, and atenolol. The following protocols were performed: (i) determination of hemodynamics and infarct size (control = 8, phenol =6, atenolol =6), (ii) determination of interstitial NE concentrations during ischemia and reperfusion (control =7, phenol =4, atenolol =4), and (iii) electron paramagnetic resonance (EPR) study (control =6, phenol =7). One week before coronary ligation, regional cardiac denervation was performed by painting a solution of 10% phenol in ethanol on the left ventricular (LV) epicardium around the proximal region of the left coronary artery. 15 The 1-selective adrenoceptor blockade, atenolol (0.5 mg/kg), was Background Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemiareperfusion, so the influence of sympathetic denervation on myocardial ischemia -reperfusion injury was investigated in the present study. Methods and ResultsCardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously a...
Background: Increased oxidative stress might contribute to diabetic (DM) neuropathy, so the effects of longterm treatment with fluvastatin (FL) on myocardial oxidative stress and cardiac sympathetic neural function were investigated in diabetic rats.Methods and Results: FL (10 mg · kg -1 · day -1 , DM-FL) or vehicle (DM-VE) was orally administered for 2 weeks to streptozotocin-induced DM rats. Cardiac oxidative stress was determined by myocardial 8-iso-prostaglandin F2α (PGF2α) and NADPH oxidase subunit p22 phox mRNA expression. Sympathetic neural function was quantified by autoradiography using 131 I- and 125 I-metaiodobenzylguanidine (MIBG). FL did not affect plasma glucose levels but remarkably decreased PGF2α levels compared with DM-VE rats (13.8±9.2 vs 175.0±93.9 ng/g tissue), although PGF2α levels were below the detection limit in non-DM rats. FL significantly reduced myocardial p22 phox mRNA expression. Cardiac 131 I-MIBG uptake was lower in DM-VE rats than in non-DM rats, but the decrease was attenuated in DM-FL rats (1.31±0.08, 1.88±0.22, and 1.58±0.18 %kg dose/g, respectively, P<0.01). Cardiac MIBG clearance was not affected by the induction of DM or by FL, indicating that the reduced MIBG uptake in DM rats might result from impaired neural function. Diabetes-Induced Cardiac NeuropathyExperimental Animals DM was induced in male Wistar rats weighing 250-300 g by an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ, n=40). Non-DM control rats (n=14) were not injected with STZ. The rats with glucose levels >250 mg/dl at 1 week after STZ injection were considered diabetic (n=28) and used in the experiments. Two weeks later, fluvastatin (10 mg · kg -1 · day -1 , n=14) or vehicle (DM controls: 0.1% carboxymethyl cellulose, n=14) was orally administered by gavage for 2 weeks. Standard rat chow and tap water were provided ad libitum throughout the study.Systolic blood pressure and heart rate were measured using an indirect tail-cuff method (BP-98A, Softron) and lipid peroxides (LPO) in plasma were determined using a hemoglobin-methylene blue method that selectively detects the absolute quantity of LOOH. Cardiac oxidative stress was then assessed as the levels of 8-isoprostaglandin F2α (PGF2α) and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase subunit p22 phox mRNA expression, and cardiac sympathetic neural function was assessed using 131 I-and 125 Ilabeled MIBG.Radioactive MIBG Tracers FUJIFILM RI Pharma Co Ltd (Tokyo, Japan) prepared and supplied 131 I-and 125 I-labeled MIBG at a radiochemical purity >98%, and specific activity of 30-70 GBq/mmol. Cardiac MIBG AccumulationDual-tracer autoradiography proceeded as described. 22,23 Briefly, 0.37 MBq of 125 I-MIBG was injected via the external jugular vein under pentobarbital sodium anesthesia (30 mg/kg, ip). Two hours later, 1.85 MBq of 131 I-MIBG was intravenously injected and 30 min thereafter, the heart was removed and washed in cold saline. Specimens were frozen in isopentane, cooled in dry ice, embedded in methyl cellulose and cut in...
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