Fluvastatin

Fluvastatin is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMGCR), the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Human hepatocellular carcinoma cell (HCC) studies indicate that Fluvastatin induces G2/M phase arrest. In the presence of Fluvastatin, HCC cells show a decrease of Bcl-2 and procaspase-9 expression, and an increase in Bax, cleaved caspase-3, and cytochrome c. Fluvastatin is antilipemic and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.

Release properties of atelocollagen-gelatin complexes as carriers for local administration of fluvastatin.[Pubmed:28302944]

Dent Mater J. 2017 Jul 26;36(4):408-414.

The aim of this study was to investigate properties of atelocollagen/gelatin complexes (AC/Gel) and their characteristics of sustained statin release, to assess the utility of AC/Gel. AC/Gel were prepared by changing the mixing ratio of AC (0 to 40% of AC). Analysis of spectra of Fluvastatin (Flu), gelatin (Gel), and Flu with Gel complex using a Fourier transform-infrared spectrometer indicates that Flu was bound to Gel through a bond involving the carboxyl and amino groups. Evaluation of characteristics of sustained release of Flu from the AC/Gel using an ultraviolet-visible spectrophotometer showed that the release rate of Flu decreased with increasing the AC content. The histological evaluation using of Sprague-Dawley rats suggest that, unlike the pure Gel sponge, the AC/Gel was not absorbed in an early stage. Therefore, the present study showed that sustained Flu release can be controlled by using an AC/Gel, suggesting the utility of this composite material.

Single intra-articular injection of fluvastatin-PLGA microspheres reduces cartilage degradation in rabbits with experimental osteoarthritis.[Pubmed:28303595]

J Orthop Res. 2017 Nov;35(11):2465-2475.

Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of the mevalonate pathway. The anti-inflammatory effect of statins has been reported in recent years. The present study investigated therapeutic effects of the local administration of statin in osteoarthritis (OA). We assessed clinically used statins and selected Fluvastatin for further experimentation, as it showed potent anabolic and anti-catabolic effects on human OA chondrocytes. To achieve controlled intra-articular administration of statin, we developed an intra-articular injectable statin using poly(lactic-co-glycolic acid) (PLGA) as a drug delivery system (DDS). The release profile of the statin was evaluated in vitro. Finally, therapeutic effects of Fluvastatin-loaded PLGA microspheres (FLU-PLGA) were tested in a rabbit OA model. Rabbit knees were divided into four subgroups: group 1-A, PLGA-treated group; group 1-B, PLGA contralateral saline control group; group 2-A, FLU-PLGA-treated group; and group 2-B, FLU-PLGA contralateral saline control group. Histological analysis 5 weeks after intra-articular injection revealed that OARSI scores were lower in group 2-A. No significant differences in OARSI scores were observed between groups 1-A, 1-B, and 2-B. This study indicates that a single intra-articular injection of Fluvastatin-loaded PLGA microspheres could be a novel therapeutic approach for treating patients with OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2465-2475, 2017.

Protective Effects of Fluvastatin on Reproductive Function in Obese Male Rats Induced by High-Fat Diet through Enhanced Signaling of mTOR.[Pubmed:28214901]

Cell Physiol Biochem. 2017;41(2):598-608.

BACKGROUND: Statins can reduce reproductive damage induced by obesity or high-fat diet (HFD), but the specific regulatory mechanisms are largely unknown. Since mTOR/p70s6k sinaling promotes spermatogonia proliferation and spermatogenesis, we hypothesized that this pathway will be involved in the protective effects of statin in HFD-induced reproductive dysfunction. METHODS: Male Sprague Dawley rats (3 weeks old) were randomly divided into a control group (standard diet), HFD group, and a Fluvastatin group (HFD + Fluvastatin at 6mg/kg, once daily by oral gavage). After 8 weeks, body weight was obtain and rats were sacrificed. Weights of the testes, gross morphology, sperm parameters, circulating levels of sex hormones, lipid levels, and tissue mTOR, p-P70s6k were measured. Another set of male rats were treated with rapamycin or vehicle. Flow cytometry was used to detect the spermatogonia marker c-kit and cell cycle. p-P70s6k expression was analyzed by Western blot. RESULTS: HFD not only results in rat obesity but also leads to spermatogenetic damage and Fluvastatin was able to partially block the effects of HFD. Fluvastatin also partially reversed the suppression of mTOR and p-p70s6k expresson. CONCLUSION: Our data suggest that Fluvastatin has protective effects on reproductive function in obese male rats most probably through enhanced signaling of mTOR.

Identification and characterization of fluvastatin metabolites in rats by UHPLC/Q-TOF/MS/MS and in silico toxicological screening of the metabolites.[Pubmed:28295913]

J Mass Spectrom. 2017 May;52(5):296-314.

The present study reports the in vivo and in vitro identification and characterization of metabolites of Fluvastatin, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, using liquid chromatography-mass spectrometry (LC-MS). In vitro studies were conducted by incubating the drug with human liver microsomes and rat liver microsomes. In vivo studies were carried out by administration of the drug in the form of suspension to the Sprague-Dawley rats followed by collection of urine, faeces and blood at different time points up to 24 h. Further, samples were prepared by optimized sample preparation method, which includes freeze liquid extraction, protein precipitation and solid phase extraction. The extracted and concentrated samples were analysed using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. A total of 15 metabolites were observed in urine, which includes hydroxyl, sulphated, desisopropyl, dehydrogenated, dehydroxylated and glucuronide metabolites. A few of the metabolites were also present in faeces and plasma samples. In in vitro studies, a few metabolites were observed that were also present in in vivo samples. All the metabolites were characterized using ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry in combination with accurate mass measurement. Finally, in silico toxicity studies indicated that some of the metabolites show or possess carcinogenicity and skin sensitization. Several metabolites that were identified in rats are proposed to have toxicological significance on the basis of in silico evaluation. However, these metabolites are of no human relevance. Copyright (c) 2017 John Wiley & Sons, Ltd.

Fluvastatin (XU 62-320 free acid) is a first fully synthetic, competitive HMG-CoA reductase inhibitor with an IC50 of 8 nM. Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant pathway.

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