• The Korean Journal of Physiology and Pharmacology
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• v.17 no.3
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• pp.245-251
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• 2013

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration($IC_{50}$) of 4.1 ${\mu}M$ and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the $AUC_{0-{\infty}}$ of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.

• YAKHAK HOEJI
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• v.50 no.2
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• pp.118-123
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• 2006

The aim of this study was to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were deter-mined after an oral administration of diltiazem (15 mg/kg) to rats pretreated with fluvastatin (0.5 and 1.5 mg/kg). Compared with the control (given diltiazem alone), the pretreatment of fluvastatin significantly (p<0.05) increased the area under the plasma concentration (AUC), peak plasma concentration $(C_{max})\;and\;K_a$ of diltiazem. Relative bioavailability $(RB\%)$ of diltiazem increased from 1.36- to 1.55-fold. However there were no significant changes in $t_{max},\;K_{el}\;and\;t_{1/2}$ of diltiazem. The pretreatment of fluvastatin also altered the pharmacokintic parameters of desacetyldiltiazem. The pretreatment of fluvastatin (1.5 mg/kg) significantly (p<0.05) increased the AUC of desacetyldiltiazem, whereas the metabolite parent ratio (MR) of desacetyldiatlazem was decreased significantly (p<0.05), suggesting that fluvastatin might inhibit the metabolism of diltiazem. The pretreatment of fluvastatin enhanced the bioavailability of diltiazem in a dose dependent manner at doses ranging from 0.5 to 1.5 mg/kg. further studies for the drug Interaction will be needed in the clinical trials when dilitazem is administrated concomitantly with fluvastatin in humans.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.193-201
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• 2018

Connective tissue growth factor (CTGF) is a novel fibrotic mediator, which is considered to mediate fibrosis through extracellular matrix (ECM) synthesis in diabetic cardiovascular complications. Statins have significant immunomodulatory effects and reduce vascular injury. We therefore examined whether fluvastatin has anti-fibrotic effects in vascular smooth muscle cells (VSMCs) and elucidated its putative transduction signals. We show that advanced glycation end products (AGEs) stimulated CTGF mRNA and protein expression in a time-dependent manner. AGE-induced CTGF expression was mediated via ERK1/2, JNK, and Egr-1 pathways, but not p38; consequently, cell proliferation and migration and ECM accumulation were regulated by CTGF signaling pathway. AGE-stimulated VSMC proliferation, migration, and ECM accumulation were blocked by fluvastatin. However, the inhibitory effect of fluvastatin was restored by administration of CTGF recombinant protein. AGE-induced VSMC proliferation was dependent on cell cycle arrest, thereby increasing G1/G0 phase. Fluvastatin repressed cell cycle regulatory genes cyclin D1 and Cdk4 and augmented cyclin-dependent kinase inhibitors p27 and p21 in AGE-induced VSMCs. Taken together, fluvastatin suppressed AGE-induced VSMC proliferation, migration, and ECM accumulation by targeting CTGF signaling mechanism. These findings might be evidence for CTGF as a potential therapeutic target in diabetic vasculature complication.

• Bulletin of the Korean Chemical Society
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• v.32 no.10
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• pp.3748-3751
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• 2011

• Journal of Life Science
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• v.31 no.4
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• pp.418-424
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• 2021

Skin inflammation (dermatitis) is caused by varying skin damage due to ultraviolet radiation and microbial infection. Currently prescribed drugs for dermatitis include anti-histamine and steroid drug classes that soothe inflammation. However, incorrect or prolonged use of steroids can cause weakening of skin barriers as well as osteoporosis. Therefore, treating dermatitis with a drug that has minimal side effects is important. Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are cholesterol-lowering drugs that have been widely treated for hyperlipidemia and cardiovascular diseases. Interestingly, recent studies have shown the anti-inflammatory effects of statins in both experimental and clinical models for of osteoarthritis. This study investigated the possible anti-inflammatory effects of atorvastatin and fluvastatin in human keratinocytes (HaCaT cells), which are crucial components of skin barriers. Stimulation of HaCaT cells with IL-1β increased the expression of the COX2 protein, a major player of inflammatory responses. However, this induction of the COX2 protein was downregulated by pretreatments with atorvastatin and fluvastatin. Treatment with IL-1ß-induced the upregulation of other inflammatory genes (such as iNOS and MMP-1) and these expressions were similarly lowered by these two statin drug treatments. Taken together, these results indicated that atorvastatin and fluvastatin can reduce IL-1β-induced inflammatory responses in HaCaT cells. In conclusion, the findings suggest that atorvastatin and fluvastatin can be potential modulators for ameliorating skin inflammation.

• The Korea Journal of Herbology
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• v.30 no.6
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• pp.69-75
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• 2015

Objectives : This study was designed to investigate effects of the combination with Korean Red Ginseng (Panax ginseng C.A. Meyer), Gastrodia Rhizoma (Gastrodia elata Blume) and Polygoni Multiflori Radix (Polygonum multiflorum Thunberg) on metabolic disorders including cholesterol and erectile dysfunction in hyperlipidemia rats.Methods : Animals were divided into six groups; Control with normal diet, high fat/cholesterol-diet (HFCD), fluvastatin, Korean Red Ginseng treated (KRG), and the combination treated (Korean Red Ginseng, Gastrodia Rhizoma and Polygoni Multiflori Radix; 1:1:1 for KGP1 and 2:1:1 for KGP2). The experimental groups initially received HFCD for 10 weeks and then treated orally with fluvastatin, KRG, KGP1 and KGP2 during the final 6 weeks. Erectile function was determined by the measurements of intracavernosal pressure (ICP) and maximal arterial pressure (MAP) after electrical stimulation of the cavernosal nerve.Results : KGP2 decreased the level of total cholesterol and LDL cholesterol in the sera of HFCD rats without no changes of body weights. KRG, KGP1 and KGP2 decreased the level of C-reactive protein (CRP) levels except of fluvastatin, synthetic HMG-CoA reductase inhibitor. KRG, KGP1 and KGP2 significantly increased the ICP, ICP/MAP ratio, area under the curve (AUC) compared with those of normal rat. Morphometric analyses showed that KRG, KGP1 and KGP2 increased the volume of smooth muscle and the regular arrangement of collagen fibers in corpus cavernosum of HFCD rats. The penile expression of eNOS was increased by KRG, KGP1 and KGP2.Conclusions : Based on these results, we suggest that the combination with Korean Red Ginseng, Gastrodia Rhizoma and Polygoni Multiflori may improve hyperlipidemia through regulating the lipid profiles and erectile dysfunction in rats.

• Journal of Korean Society of Environmental Engineers
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• v.39 no.3
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• pp.124-131
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• 2017

In this study, We investigated the effects of water temperature and empty bed contact time (EBCT) on the biodegradability of 8 blood lipid lower agents (BLLAs) in biological activated carbon (BAC) process. Experiments were conducted at three water temperatures ($8^{\circ}C$, $16^{\circ}C$ and $24^{\circ}C$) and three EBCTs (5 min, 10 min and 15 min). Increasing water temperature and EBCT increased the biodegradation efficiency of BLLAs in BAC process. Simvastatin and fenofibrate were the highest biodegradation efficiency, but atorvastatin and clofibric acid were the lowest. The kinetic analysis suggested a pseudo-first-order reaction model for biodegradation of 8 BLLAs at various water temperatures and EBCTs. The pseudo-first-order biodegradation rate constants ($k_{bio}$) of clofibric acid and atorvastatin were $0.0075min^{-1}$ and $0.0122min^{-1}$ at $8^{\circ}C$, and were $0.0540min^{-1}$ and $0.0866min^{-1}$ at $24^{\circ}C$, respectively. By increasing the water temperature from $8^{\circ}C$ to $24^{\circ}C$, the biodegradation rate constants ($k_{bio}$) were increased 7.1~7.2 times.

• Journal of Physiology & Pathology in Korean Medicine
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• v.32 no.1
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• pp.43-50
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• 2018

Korean Red Ginseng (RG) are used as a traditional treatment for improve blood circulation. This experimental study was designed to investigate the inhibitory effects of Korean red ginseng on lipid metabolism in high fat/cholesterol diet (HFCD)-induced hypertriglyceridemia. Sprague Dawley rats were fed the HFCD diet with/without fluvastatin (Flu, positive control) 3 mg/kg/day, and RG 125 or 250 mg/kg/day, respectively. All groups received regular diet or HFCD diet, respectively, for 13 weeks. The last three groups treatment of Flu and RG 125, and RG 250 orally for a period of 9 weeks. Group 1, reular diet; group 2, HFCD diet; group 3, Flu + HFCD diet; group 4, RG 125 + HFCD diet; group 5, RG 250 + HFCD diet. As a result, treatment with low or high doses of RG markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. RG and Flu also led to an increase in lipoprotein lipase activity in the HFCD group. On the other hand, RG and Flu led to an decrease in fatty acid synthase and free fatty acid activity in the HFCD group. Treatment with RG suppressed increased expressions of $PPAR-{\alpha}$ and AMPK in HFCD rat liver or muscle. In addition, the RG attenuated triglyceridemia by inhibition of $PPAR-{\gamma}$ and FABP protein expression levels and LXR and SREBP-1 gene expression in liver or muscle. The RG significantly prevented the development of the metabolic disturbances such as hypertriglyceridemia and hyperlipidemia. Taken together, the administration of RG improves hypertriglyceridemia through the alteration in suppression of triglyceride synthesis and accentuated of triglyceride decomposition. These results suggested that RG is useful in the prevention or treatment of hypertriglyceridemia.