Pitavastatin Calcium

Pitavastatin Calcium is a competitive inhibitor of the enzyme HMGCR (HMG-CoA reductase) results in a reduction in LDL cholesterol synthesis. Alternate studies show that pitavastatin can suppress oxygen production in endothelial cells by inhibiting NADPH oxidase. In addition, pitavastatin reduces the expression of eNOS mRNA while increasing the NO dependent response stimulated by acetylcholine and the calcium ionophore, A23187. Furthermore, pitavastatin inhibits the up-regulation of conductance calcium-activated potassium channels by lowering cholesterol levels in cells.

Pitavastatin calcium improves endothelial function and delays the progress of atherosclerosis in patients with hypercholesterolemia.[Pubmed:25990055]

J Zhejiang Univ Sci B. 2015 May;16(5):380-7.

BACKGROUND: Statins have proven efficacy in inhibiting the onset and progress of atherosclerosis. The effectiveness of pitavastatin in reversing carotid atherosclerosis associated with hypercholesterolemia (HC) is unknown. OBJECTIVES: To explore the simultaneous effects of Pitavastatin Calcium on brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and arterial stiffness (beta), three surrogate markers of atherosclerosis were studied in HC patients. METHODS: A randomized, double-blind trial was performed with 40 HC subjects who fulfilled the inclusion/exclusion criteria. Patients were given Pitavastatin Calcium 1 mg/d (Group 1) or 2 mg/d (Group 2) for 8 weeks. There were 20 patients in each group, and 30 gender- and age-matched healthy subjects as controls were recruited. FMD of the brachial artery, carotid IMT, and arterial stiffness indicated by beta were measured at baseline and at 8 weeks after starting Pitavastatin Calcium therapy using ultrasound techniques. Biochemical tests were also made on all subjects. RESULTS: At baseline, higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), reduced FMD, and increased beta and IMT were observed in HC patients (P<0.001 for all) compared with controls. After 8 weeks, TC was decreased by 20.59%/27.56% and LDL-C 30.92%/35.64%, respectively, in comparison to baseline groups; the HC groups had reduced beta and improved endothelial function over the 8-week follow-up (P<0.05-0.001); nonetheless, no significant alterations of IMT were found (P>0.05). Significant negative interactions between TC/LDL and FMD (P<0.05-0.001), positive interactions between TC and IMT (P=0.003) and between TC/LDL and beta (P<0.001-0.000) were found. CONCLUSIONS: Treatment with Pitavastatin Calcium exerted favorable effects on endothelial function and arterial stiffness. It also improved carotid atherosclerosis in patients with HC.

Diastereoselective synthesis of pitavastatin calcium via bismuth-catalyzed two-component hemiacetal/oxa-Michael addition reaction.[Pubmed:26275074]

Org Biomol Chem. 2015 Oct 14;13(38):9813-9.

An efficient and concise asymmetric synthesis of Pitavastatin Calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavastatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-alpha,beta-unsaturated ketone 4 with acetaldehyde.

Pharmacokinetic Properties of Single- and Multiple-Dose Pitavastatin Calcium Tablets in Healthy Chinese Volunteers.[Pubmed:26082816]

Curr Ther Res Clin Exp. 2015 Mar 3;77:52-7.

BACKGROUND: Pitavastatin is a newly developed 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor approved for the treatment of hyperlipidemia. Pharmacokinetic properties of pitavastatin have been studied previously. OBJECTIVE: To investigate the pharmacokinetic properties of pitavastatin in healthy Chinese volunteers after single-dose and multiple-dose administration. METHODS: An open-label, randomized, single-dose and multiple-dose study was conducted in healthy Chinese volunteers. The study included 4 stages, each separated with a 5-day washout period. A randomized, 3-way crossover design was carried out in Stages 1 to 3 for the single-dose study. Eligible subjects were randomized to receive a single 1 mg, 2 mg, or 4 mg Pitavastatin Calcium tablet. Blood samples were obtained predose and up to 36 hours following dosing. In Stage 4 the subjects received a 2-mg Pitavastatin Calcium tablet once daily for 6 days. At the last day of multiple dosing, blood samples were collected predose and up to 48 hours following dosing. Plasma pitavastatin was quantified by a validated liquid chromatography tandem mass spectrometry method. Tolerability was assessed by the adverse events, physical examination, 12-lead ECG, and laboratory tests. RESULTS: Twelve volunteers (6 male and 6 female) were enrolled in the study and 11 of them completed all 4 study stages. Following a single dose of 1 mg, 2 mg, and 4 mg, the mean (SD) Tmax values were 0.63 (0.17) hours, 0.65 (0.17) hours, and 0.79 (0.36) hours, respectively; the corresponding Cmax values were 66.80 (16.32) ng/mL, 106.09 (31.59) ng/mL, and 232.91 (66.42) ng/mL, respectively. AUC0-36 values were 190.04 (38.97) ng/mL/h, 307.87 (57.94) ng/mL/h, and 785.10 (166.08) ng/mL/h, respectively, whereas t1/2 values were 10.99 (2.70) hours, 9.52 (2.58) hours, and 10.38 (4.28) hours, respectively. The AUC and Cmax showed dose proportionality after single dosing according to linear-regression analysis. In the multiple-dose study, a rapid absorption (Tmax of 0.68 [0.20] hours) and marked peak concentration of 90.99 (36.88) ng/mL were observed. AUC0-48 and AUCss were 306.28 (130.02) ng/mL/h and 256.16 (116.34) ng/mL/h, respectively. The elimination half-life after multiple dosing was significantly prolonged, which amounted to 13.31 (2.58) hours. Comparison of the pharmacokinetic parameters between the male and female groups revealed no significant differences. CONCLUSIONS: In healthy Chinese volunteers, single dosing of 1 mg, 2 mg, and 4 mg pitavastatin resulted in linear plasma pharmacokinetic properties. Compared with single dosing, multiple dosing of pitavastatin showed different distribution and elimination characteristics. Sex did not appear to affect the pharmacokinetic properties of pitavastatin. Chictr.org identifier: ChiCTR-OO-13004294.

The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects.[Pubmed:26186644]

Xenobiotica. 2016;46(1):34-9.

1. Pitavastatin is an effective treatment for primary hyperlipidemia and mixed dyslipidemia. The aim of the present study was to investigate the effect of food on the pharmacokinetic properties and bioequivalence of the original, branded, formulation of Pitavastatin Calcium and a new generic formulation in healthy Chinese male subjects under fasting and fed conditions. 2. Under fasting and fed conditions, 90% CIs of the geometric mean of generic/branded AUC0-48 h ratios were 92.2-102.4%, 93.1-104.5%, the ratios of ln(AUC0-infinity) were 92.6-103.7%, 93.2-103.5%, and ln(Cmax) ratios were 90.7-110.3%, 84.7-100.8%, respectively. The generic and branded formulations were bioequivalent in terms of rate and extent of absorption under both the conditions. The average values of AUC0-48 h, AUC0-infinity and Cmax decreased noticeably following a high-fat breakfast. Values for AUC0-48 h were 87.69% and 83.7%, values for AUC0-infinity were 87.5% and 84.6%, and values for Cmax were 45.0% and 50.4% in subjects given the generic and branded preparations, respectively. The absorption of Pitavastatin Calcium tablets was delayed following a high-fat meal, with Tmax increasing by up to 2.43-fold. 3. Both formulations were generally well tolerated, with no serious adverse reactions reported. The newly developed generic formulation may provide a reliable alternative to the branded tablets for patients with primary hyperlipidemia or mixed dyslipidemia.

Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.[Pubmed:16810078]

J Cardiovasc Pharmacol. 2006 Jun;47(6):770-9.

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.

Pitavastatin.[Pubmed:15854203]

Int J Clin Pract. 2005 Feb;59(2):239-52.

The growing number of trials that have highlighted the benefit of intensive lowering of total- and low density lipoprotein (LDL)-cholesterol levels especially with statins has created a need for more efficacious agents. Pitavastatin is a new synthetic 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor, which was developed, and has been available in Japan since July 2003. Metabolism of pitavastatin by the cytochrome P450 (CYP) system is minimal, principally through CYP 2C9, with little involvement of the CYP 3A4 isoenzyme, potentially reducing the risk of drug-drug interactions between pitavastatin and other drugs known to inhibit CYP enzymes. To date, human and animal studies have shown pitavastatin to be potentially as effective in lowering LDL-cholesterol levels as rosuvastatin; although, head-to-head studies are yet to be conducted.

Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.[Pubmed:9296275]

Arzneimittelforschung. 1997 Aug;47(8):904-9.

Pharmacological properties of NK-104 ((+)-monocalcium bis inverted question mark(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl++ +]-3,5-dihydroxy-6- heptenoate inverted question mark, CAS 147526-32-7), a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, were investigated. The kinetic study, using rat liver microsomal HMG-CoA reductase, revealed that NK-104 is a competitive inhibitor of HMG-CoA reductase with a Ki of 1.7 nmol/l. To examine the inhibitory effect on sterol synthesis in vivo, de novo synthesis of sterols from [14C]acetate 3 h after oral administration of NK-104 was measured in rats. NK-104 showed marked inhibition in liver (ED50 0.13 mg/kg) and in ileum (ED50 0.20 mg/kg), but much weaker in the other tissues. The inhibitory effect of NK-104 on liver sterol synthesis lasted over 6 h, while that of pravastatin and simvastatin disappeared 6 h after administration of the drugs twice the ED50s. Due to induction of HMG-CoA reductase, initial suppression of hepatic sterol synthesis by pravastatin and simvastatin was compensated, and the cumulative change in hepatic sterol synthesis during 12 h after drug administration was remarkably negative only with long-acting NK-104. Hypolipidemic effects of NK-104 (0.03, 0.1, 0.3 and 1 mg/kg p.o. for 2 weeks) were examined in beagle dogs. NK-104 reduced plasma total cholesterol dose-dependently (13.1, 18.5 and 20.2% at doses of 0.1, 0.3 and 1 mg/kg, respectively), and also plasma triglycerides by 0.1 mg/kg or more. Pravastatin (1 and 3 mg/kg) and simvastatin (3 mg/kg) lowered plasma total cholesterol (14.0, 15.4 and 17.4%, respectively), but did not significantly affect plasma triglyceride levels. These results indicate that NK-104 is a potent, liver-selective, long-acting HMG-CoA reductase inhibitor with a high cholesterol- and triglyceride-lowering potency.

Pitavastatin Calcium (NK-104 hemicalcium) is a potent hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor. Pitavastatin Calcium (NK-104 hemicalcium) inhibits cholesterol synthesis from acetic acid with an IC50 of 5.8 nM in HepG2 cells. Pitavastatin Calcium is an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Anti-cancer activity.

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