• Korean Journal of Clinical Pharmacy
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• v.20 no.1
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• pp.25-29
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• 2010

The purpose of this study was to investigate the effect of atorvastatin on the pharmacokinetics of nifedipine (6 mg/kg) after oral administration of nifedipine with or without atorvastatin (0.5 and 2.0 mg/kg) in rats, and also was to evaluate to the effect of atorvastatin on the CYP3A4 activity. The 50% inhibiting concentration ($IC_{50}$) values of atorvastatin on CYP3A4 activity is 46.1 ${\mu}M$. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner. Coadministration of atorvastatin increased significantly (p<0.05, 2.0 mg/kg) the plasma concentration-time curve (AUC) and the peak concentration ($C_{max}$) of nifedipine compared to the control group. The relative bioavailability (RB%) of nifedipine was increased from 1.15- to 1.37-fold. Coadministration of atorvastatin did not significantly change the terminal half-life ($T_{1/2}$) and the time to reach the peak concentration ($T_{max}$) of nifedipine. Based on these results, we can make a conclusion that the significant changes of these pharmacokinetic parameters might be due to atorvastatin, which possesses the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein (P-gp) efflux pump in the intestinal mucosa. It might be suggested that atorvastatin altered disposition of nifedipine by inhibition of both the first-pass metabolism and P-glycoprotein efflux pump in the small intestine of rats. In conclusion, the presence of atorvastatin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of atorvastatin with nifedipine should require close monitoring for potential drug interation.

• Korean Journal of Clinical Pharmacy
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• v.23 no.4
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• pp.316-321
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• 2013

Purpose: Atorvastatin, a HMG-CoA reductase inhibitor is widely prescribed in hyperlipidemic patients and telmisartan, an angiotensin receptor blocker is frequently used in the treatment of hypertension. Both drugs are substrates of organic anion transporting polypeptide (OATP) expressed in basolateral membrane in the liver, and undergo high first pass metabolism. Therefore, OATP-mediated hepatic uptake is important for disposition and metabolism of these drugs. The present study was designed to investigate the pharmacokinetic interactions between atorvastatin and telmisartan in rats. Method: Young adult SD rats were divided into three groups (n=6, each) and atorvastatin (10 mg/kg) and telmisartan (4 mg/kg) were orally given alone and together. Heparinized blood was serially taken and plasma concentrations of both drugs were measured using HPLC-MS/MS. Pharmacokinetic parameters of two drugs were calculated. Results: No significant pharmacokinetic change was found except a delay of time to peak of telmisartan when administered with atorvastatin. Each drug at the present dosage seemed to be insufficient to alter the pharmacokinetic parameters of its counterpart drug. Conclusion: Conclusively, co-administration of atorvastatin and telmisartan may lead to negligible clinical consequences.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.367-375
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• 2022

Gastric cancer stem cells (GCSCs) are a major cause of radioresistance and chemoresistance in gastric cancer (GC). Therefore, targeting GCSCs is regarded as a powerful strategy for the effective treatment of GC. Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme in the mevalonate pathway. The anticancer activity of atorvastatin, a repurposed drug, is being investigated; however, its therapeutic effect and molecular mechanism of action against GCSCs remain unknown. In this study, we evaluated the anticancer effects of atorvastatin on MKN45-derived GCSCs. Atorvastatin significantly inhibited the proliferative and tumorsphere-forming abilities of MKN45 GCSCs in a mevalonate pathway-independent manner. Atorvastatin induced cell cycle arrest at the G0/G1 phase and promoted apoptosis by activating the caspase cascade. Furthermore, atorvastatin exerted an antiproliferative effect against MKN45 GCSCs by inhibiting the expression of cancer stemness markers, such as CD133, CD44, integrin α6, aldehyde dehydrogenase 1A1, Oct4, Sox2, and Nanog, through the downregulation of β-catenin, signal transducer and activator of transcription 3, and protein kinase B activities. Additionally, the combined treatment of atorvastatin and sorafenib, a multi-kinase targeted anticancer drug, synergistically suppressed not only the proliferation and tumorsphere formation of MKN45 GCSCs but also the in vivo tumor growth in a chick chorioallantoic membrane model implanted with MKN45 GCSCs. These findings suggest that atorvastatin can therapeutically eliminate GCSCs.

• Korean Journal of Clinical Pharmacy
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• v.17 no.1
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• pp.33-37
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• 2007

The purpose of this study was to investigate the effect of atorvastatin on the pharmacokinetics of diltiazem (15 mg/kg) after oral administration of diltiazem with or without atorvastatin (0.5, 1.5 and 3.0 mg/kg) in rats. Coadministration of atorvastatin increased significantly (p<0.05, 3.0 mg/kg) the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of diltiazem compared to the control group. The total plasma clearance (CL/F) of diltiazem was decreased significantly (p<0.05, 3.0 mg/kg) compared to the control group. The relative bioavailability (RB%) of diltiazem was increased from 1.14- to 1.49-fold. Coadministration of atorvastatin did not significantly change the elimination rate constant $(K_{el})$, terminal half-life $(T_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of diltiazem. Based on these results, we can make a conclusion that the significant changes of these pharmacokinetic parameters might be due to atorvastatin, which possesses the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein (P-gp) efflux pump in the intestinal mucosa.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.12 no.11
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• pp.4940-4950
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• 2011

cis-(3R,5R)-Atorvastatin Ca (1) used for hyperlipidemia have four stereomers. However, It is very difficult to prepare stereoselective stereomers. In this paper, the reduction of 3,5-diketo atorvastatin ester (3) was performed using $Me_4NHB(OAc)_3$ in acetic acid as a reductant and showed excellent stereoselectivity in the double reduction of 3,5-diketo atorvastatin ester (3). As a result, reduction of compound 3 by $Me_4NHB(OAc)_3$ was purely obtained with cis-(3R,5R)-atorvastatin ester (4) of 1.5% and trans-(3R,5S)-atorvastatin ester (5) of 98.5%. Also, cis-(3R,5R)-atorvastatin Ca (1) and trans-(3R,5S)-atorvastatin Ca (7) were used to determine efficacy in the treatment of liver damage and hyperlipidemia induced by a high-fat diet in rats and to study the performance of the January 2010 experient was conducted. As a result, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), and triglyceride (TG) levels of compound 1 and 7 groups were $93.0{\pm}0.5$, $43.5{\pm}0.8$, $40.4{\pm}1.4$, $45.6{\pm}0.9\;mg/d{\ell}$ and $110.0{\pm}0.7$, $33.3{\pm}0.6$, $65.8{\pm}1.9$, $54.8{\pm}1.2\;mg/d{\ell}$, respectively. Atherogenic index (AI) and cardiac risk factor (CRF) in compound 1 and 7 were $1.14{\pm}0.05$, $2.14{\pm}0.05$ and $2.31{\pm}0.06$, $3.31{\pm}0.06$, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were $51.9{\pm}4.6$, $16.0{\pm}2.1\;IU/{\ell}$ and $75.8{\pm}4.4$, $35.1{\pm}9.7\;IU/{\ell}$. Taken together, while compound 1 treat against high-fat diet-induced hyperlipidemia by attenuating hepatic lipid depots and reducing oxidative stress, compound 7 group had a low curative effect on hyperlipidemia induced by a high-fat diet in rats. These findings suggest that new method about synthesis of stereoselective stereomers and indicate that it may consider using in a clinical trial.

• Biomolecules & Therapeutics
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• v.16 no.1
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• pp.54-60
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• 2008

Dyslipidemia is the multiple lipid metabolic disorders which is one of the high risk factors for the atherosclerotic diseases. It increases the morbidity and mortality and therefore, must be treated with antilipidemic agents. HMG-Co A reductase inhibitors (statins), one of many antidyslipidemic agents, have shown to be significant improvement from the various cholesterol levels. Especially, data from many comparative trials suggest that rosuvastatin is more effective than atorvastatin among many other statins. The aims of this study were to evaluate the efficacy and safety between rosuvastatin and atorvastatin in the treatment of Korean patients with dyslipidemia. Currently the Korean Society of Lipidology and Atherosclerosis based on the Korean health screening data suggests that Korean patients with dyslipidemia should be treated by the target cholesterol levels according to the Adult Treatment Panel III guidelines of the US National Cholesterol Education Program (NCEP-ATP III). We reviewed retrospectively all medical histories of the total 392 dyslipidemic patients with atorvastatin or rosuvastatin from June 1st, 2004 to August 31st, 2006 in Chungbuk National University Medical Center. Patients were classified as total 4 groups by the NCEP-ATP III Guidelines. The numbers of enrolled patients were each 5 mg atorvastatin (n=34), 10 mg atorvastatin (n=148), 5 mg rosuvastatin (n=94) and 10 mg rosuvastatin (n=82). In comparison between groups, rosuvastatin groups in the lowering LDL-C had better efficacies, and the results were each 22% (5 mg atorvastatin), 33.3% (10 mg atorvastatin), 35% (5 mg rosuvastatin) and 41.3% (10 mg rosuvastatin) with the dose relationship (P=0.000). Rosuvastatin groups also have shown to be more significantly reducing Total Cholesterol levels compared to atorvastatin groups with the no dose relationship (P=0.000). In the lowering of non-HDL cholesteroles, rosuvastatin groups showed significantly better efficacies than atorvastatin with the dose-relationship (P=0.000). Each medication groups did not demonstrate the differences in the changing of HDL cholesterol and triglyceride levels (P=0.096, 0.309, respectively). In conclusion, rosuvastatin was better efficacious than atrovastatin in reducing LDL-C Total Chol, and Tg. Therefore, rosuvastatin is a good antilipidemic agents for Korean patients with dyslipidemia and it can use to minimize the morbidity and mortality related to the cardiovascular diseases in Korean.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.3
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• pp.301-309
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• 2018

Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA-induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation.

• Korean Journal of Clinical Pharmacy
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• v.29 no.2
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• pp.133-137
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• 2019

Atorvastatin is one of the most widely prescribed medications for dyslipidemia treatment. In Korea, post combined therapy with ezetimibe, a 73-year-old woman was reported by a community pharmacy to have experienced visual field defect, which recovered after drug discontinuation. She had never experienced this symptom before, and several studies have reported an association between use of statins and visual disorders such as blurred vision, diplopia, and cataract. Blockage of cholesterol accumulation, oxidative stress, or myopathy is expected to be a cause of this symptom. Naranjo scale, Korean causality assessment algorithm (Ver.2), and World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria were the three tools used to determine causality between the visual disorder and atorvastatin. The results represent 'probable', 'certain', and 'probable/likely' causality, respectively. Our results, in combination with a review of literature, indicate that ocular adverse effects are highly likely related to atorvastatin.

• Journal of Pharmaceutical Investigation
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• v.38 no.4
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• pp.249-254
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• 2008

Solid dispersions of poorly water-soluble drug, atorvastatin, were prepared with Eudragit L100 to improve the solubility by spray dryer. To investigate the correlation between physicochemical properties and dissolution rate of solid dispersions, the samples were characterized by scanning electron microscopy (SEM), differential scanning calorimeter (DSC) and fourier transform infrared spectroscopy (FT-IR). SEM and DSC were found that atorvastatin is amorphous in the Eudragit L100 solid dispersion. FT-IR was used to analyze the salt formation by interaction between atorvastatin and Eudragit L100. The dissolution rate of solid dispersed atorvastatin was markedly increased compared to drug powder in stimulated intestinal juice (pH 6.8). Thus, the solid dispersed atorvastatin using the spray drying method with Eudragit L100 may be effective for the bioavailability.

• Journal of Lipid and Atherosclerosis
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• v.5 no.1
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• pp.61-77
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• 2016

Objective: This study aims to analyze cost-effectiveness of two most-commonly used statins from the perspective of the Korean national health system. Methods: The scope of the analysis included rosuvastatin (5 mg, 10 mg, and 20 mg) and atorvastatin (10 mg, 20 mg, 40 mg, and 80 mg). Effectiveness was defined as percentage (%) and absolute (mg/dL) reductions of low-density lipoprotein cholesterol (LDL-C) from the baseline. They were derived from published randomized controlled studies for rosuvastatin and atorvastatin. Effectiveness was defined as reductions in LDL-C levels per mg dose of the drugs. The annual direct medical costs including drug acquisition costs and monitoring costs over the one-year time horizon were calculated for each alternative. The average cost-effectiveness ratios (ACERs) and incremental cost-effectiveness ratios (ICERs) for each statin dose were calculated. Results: The ACERs for all doses of rosuvastatin (5 mg, 10 mg, and 20 mg) were lower than those for all doses of atorvastatin (10 mg, 20 mg, 40 mg, and 80 mg). Rosuvastatin 10 mg was the most cost-effective statin for LDL-C reduction. In cost-effectiveness analyses for corresponding doses of rosuvastatin and atorvastatin, rosuvastatin was the superior strategy which suggests both higher effectiveness and lower costs than atorvastatin. However, we have to consider this analysis is highly influenced by current price of statins in each market. Conclusion: For reduction of LDL-C levels in Korean patients with dyslipidemia, rosuvastatin 10mg is the most cost-effective statin in the current Korean market.