Effect of Atorvastatin on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

Soon-Pyo Hong,Kyoung-Sig Chang,Dong-Hyun Choi,Jun-Shik Choi 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.1

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg·kg-1) to rats pretreated with atorvastatin (0.5 or 2.0 mg·kg-1). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p<0.05, 0.5 mg·kg-1; p<0.01, 2.0 mg·kg-1) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg·kg-1 atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg·kg-1 atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%) were significantly higher (p< 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p<0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg·kg-1) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.

Effect of Atorvastatin on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

Hong, Soon-Pyo,Chang, Kyoung-Sig,Choi, Dong-Hyun,Choi, Jun-Shik 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.1

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem $(15mg{\cdot}kg^{-1})$ to rats pretreated with atorvastatin $(0.5\;or\;2.0mg{\cdot}kg^[-1})$. Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration $(C_{max})$ and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly $(p<0.05,\;0.5mg{\cdot}kg^{-1};\;p<0.01,\;2.0mg{\cdot}kg^{-1})$ increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with $0.5mg{\cdot}kg^{-1}$ atorvastatin, and 1.77-fold in rats pretreated with $20mg{\cdot}kg^{-1}$ atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%) were significantly higher (p<0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p<0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin $(0.5\;or\;2.0mg{\cdot}kg^{-1})$ was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.

Interleukin-13으로 유도된 폐 병태생리에 대한 atorvastatin의 치료 효과

모요셉 ( Yosep Mo ),배보람 ( Boram Bae ),김정현 ( Junghyun Kim ),김율담 ( Ruth Lee Kim ),손경희 ( Kyunghee Son ),강민종 ( Min-jong Kang ),이춘근 ( Chun-gen Lee ),조상헌 ( Sang-heon Cho ),강혜련 ( Hye-ryun Kang ) 대한천식알레르기학회(구 대한알레르기학회) 2021 Allergy Asthma & Respiratory Disease Vol.9 No.2

Purpose: Asthma is a common chronic lung disease, in which interleukin (IL)-13 is implicated as a central regulator of IgE synthesis, mucus hypersecretion, airway hyperresponsiveness (AHR), and fibrosis. This study was designed to determine the anti-inflammatory effect of atorvastatin, a widely used lipid-lowering agent, on the IL-13-induced lung pathology through the modulation of macrophages. Methods: Atorvastatin (40 mg/kg) was given to transgenic mice overexpressing IL-13 (IL-13 TG mice) and their wild type littermates by oral gavage for 2 weeks. AHR, numbers of inflammatory cells in the airway, and cytokine levels in IL-13 TG mice were measured. Using the alveolar macrophage cell line CRL-2456, the direct effect of atorvastatin on macrophages activated by recombinant IL-13 was assessed. Results: Significant reduction in total leukocytes and alleviation of AHR were observed with administration of atorvastatin in IL-13 TG mice compared to those without atorvastatin treatment (P<0.05). Atorvastatin administration resulted in upregulation of IL-10 in the lungs of IL-13 TG mice (P<0.05). In addition, mRNA expression of connective tissue growth factor, fibronectin, and type III collagen as well as chord length enhanced by IL-13 overexpression were reduced by atorvastatin administration (P<0.05). M2 macrophage markers, such as Ym-1 and CD206, were decreased, while M1 macrophage marker, inducible nitric oxide synthase, was increased upon atorvastatin treatment (P<0.05). Administration of atorvastatin resulted in improved removal of apoptotic cells (P<0.05). Conclusion: The results of this study reveal a potential of atorvastatin as an effective antiasthmatic agent by reducing IL-13-induced lung inflammation via the modulation of macrophage polarization. (Allergy Asthma Respir Dis 2021;9:76-83)

대식세포 활성화 조절을 통한 atorvastatin의 항천식 효과

모요셉 ( Yosep Mo ),배보람 ( Boram Bae ),김율담 ( Yuldam Kim ),강한빛 ( Hanbit Kang ),이현승 ( Hyun Seung Lee ),조상헌 ( Sang-heon Cho ),강혜련 ( Hye-ryun Kang ) 대한천식알레르기학회(구 대한알레르기학회) 2021 Allergy Asthma & Respiratory Disease Vol.9 No.1

Purpose: Asthma is a chronic airway inflammatory disorder and is associated with macrophages. Statin, a well-known lipid-lowering agent, has recently been noted for its anti-inflammatory effect on macrophage. This study was designed to evaluate the antiasthmatic effect of atorvastatin via modulation of macrophage activation by using an animal model of allergic asthma. Methods: Atorvastatin 40 mg/kg was given by gavage once a day for 3 days before challenge of ovalbumin (OVA); airway hyperre-sponsiveness (AHR), airway inflammatory cells, and cytokines were evaluated in the murine asthma model. The direct effect of atorvastatin on the activation of macrophages in vitro was determined using the alveolar macrophage cell line CRL-2456. Results: Administration of atorvastatin reduced the numbers of total inflammatory cells, macrophages, and eosinophils as well as lung histology enhanced in the murine asthma model. AHR measured by enhanced pause was significantly reduced after atorvastatin administration in the murine asthma model (P<0.05). Atorvastatin administration resulted in the reduction in serum OVA-specific IgE levels and the increase in serum OVA-specific IgG2a levels (P<0.05). The mRNA levels of Ccr3, Il-17, and Muc5ac enhanced by OVA challenge were decreased by treatment with atorvastatin (P<0.05). Along with these improvement in allergic inflammatory changes, the population of CD11c^-CD206⁺ macrophages as well as the expression of Ym-1 and Relm-α in the lungs were reduced with atorvastatin (P<0.05). In vitro test with CRL-2456 showed that atorvastatin reduced the expression of Cd206, Arg-1, and Fgf-2 induced by IL-4 stimulation (P<0.05). Conclusion: This study highlighted the antiasthmatic effect of atorvastatin on the suppression of M2 macrophage activation in allergic asthma. (Allergy Asthma Respir Dis 2021;9:27-35)

고콜레스테롤혈증 환자에서 Atorvastation의 유용성 및 안전성에 관한 연구

고종훈,신준한,김한수,탁승제,최병일,김동수,권혁문,김현승 대한순환기학회 1999 Korean Circulation Journal Vol.29 No.9

Effect of 20 mg/day Atorvastatin: Recurrent Stroke Survey in Chinese Ischemic Stroke Patients with Prior Intracranial Hemorrhage

Weihua Jia,Lichun Zhou 대한신경과학회 2013 Journal of Clinical Neurology Vol.9 No.3

Background and Purpose Treatment with atorvastatin (80 mg) in stroke secondary prevention for patients with prior intracranial hemorrhage (ICH) has been associated with a higher frequency of ICH. The aim of this study was to determine whether 20 mg/day atorvastatin is linked to stroke recurrence in Chinese ischemic stroke patients with prior ICH. Methods A single-center retrospective cohort study was conducted, involving 354 cases from 395 Chinese in-patients who had ischemic stroke with prior ICH history in Beijing Chaoyang hospital from May 1, 2005 to October 31, 2010. Survivors were followed by telephone interviews for 12-60 months. Cox regression and Kaplan-Meier plot analysis were used to evaluate the effect of 20 mg/day atorvastatin on cerebral infarction and ICH recurrence. Results The overall rate of stroke recurrence was lower in the 20 mg/day atorvastatin group(χ2=6.687, p=0.022) than in the control group. The incidence of cerebral hemorrhage was increased by 20 mg/day atorvastatin for ischemic stroke cases with a history of ICH compared tothose not receiving the drug, but the difference was not significant [hazard ratio (HR)=1.097,95% confidence interval (CI)=0.800-1.243, p=0.980]. The incidence of ischemic stroke recurrence was significantly reduced in subjects receiving atorvastatin (HR=0.723, 95% CI=0.578-0.862, p=0.028), and the mean duration of all stroke recurrences was significantly prolonged,compared with those not exposed to the drug (χ2=5.351, p=0.021). The mean duration of ICH recurrence appeared to have shortened with atorvastatin, but the difference was not significant (χ2=0.680, p=0.480), and the mean duration of cerebral infarction recurrence was significantly prolonged (χ2=8.312, p=0.004). Conclusions Medication with 20 mg/day atorvastatin may be beneficial in reducing ischemic stroke recurrence in ischemic stroke patients with a history of ICH and is not associated with an increased risk of ICH recurrence.

Atorvastatin inhibits osteoclast differentiation by suppressing NF-κB and MAPK signaling during IL-1β-induced osteoclastogenesis

( Won-seok Lee ),( Eun-gyeong Lee ),( Myung-soon Sung ),( Yun-jung Choi ),( Wan-hee Yoo ) 대한내과학회 2018 The Korean Journal of Internal Medicine Vol.33 No.2

Background/Aims: To define the effect of statins on interleukin 1β (IL-1β)-induced osteoclastogenesis and elucidate the underlying mechanisms. Methods: Bone marrow cells were obtained from 5-week-old male ICR (Institute for Cancer Research) mice, and they were cultured to differentiate them into osteoclasts with macrophage colony-stimulating factor and the receptor activator of nuclear factor (NF)-κB ligand in the presence or absence of IL-1β or atorvastatin. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the effects of atorvastatin on osteoclastogenesis were investigated using reverse transcription polymerase chain reaction and immunoblotting for osteoclast specific molecules. Results: Atorvastatin significantly reduced the number of TRAP-positive multinucleated cells as well as the bone resorption area. Atorvastatin also downregulated the expression of the NF of activated T-cell c1 messenger RNA and inhibited the expression of osteoclast-specific genes. A possible underlying mechanism may be that atorvastatin suppresses the degradation of the inhibitors of NF-κB and blocks the activation of the c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; thus, implicating the NF-κB and mitogen-activated protein kinases pathway in this process. Conclusions: Atorvastatin is a strong inhibitor of inflammation-induced osteoclastogenesis in inflammatory joint diseases.

Puromycin을 투여한 백서에서 지질 변화가 신증의 진행에 미치는 영향

최광해,정효석,김용진,하정희,김흥식,박용훈,Choi Kwang-Hae,Chung Hyo-Seuk,Kim Yong-Jin,Ha Jeong-Hee,Kim Heung-Sik,Park Yong-Hoon 대한소아신장학회 2003 Childhood kidney diseases Vol.7 No.1

Purpose : Several studies have suggested that hyperlipidemia might be a causative factor contributing to the progression of initial glomerular injury through the development of glomerulosclerosis. We examined the potential beneficial effect of atorvastatin - which blocks the rate limiting step of cholesterol synthesis by inhibiting HMG-CoA reductase - in PAN-induced nephrosis. Materials and Methods : Glomerulosclerosis was induced in Sprague-Dawley male rats by repeated administration of PAN. Sprague-Dawley male rats were divided into 3 groups : group I(control), group II(PAN 20 mg/kg, subcutaneous injection), group III(PAN 20 mg/kg subcutaneous injection and atorvastatin 50 mg/kg/day per oral). On the 11th week, upon sacrifice of the experimental animals, blood sampling, 24-hr urine collection and nephrectomy were performed. Results : Group III had significantly lower BUN and higher serum albumin($30.9{\pm}17.2\;vs.\;17.3{\pm}2.5\;mg/dL;\;2.3{\pm}0.1\;vs.\;2.5{\pm}0.2\;g/dL$, P<0.05) compared with group II. In the lipid profiles, group III was associated with a reduction in total cholesterol and LDL($291{\pm}173\;vs.\;167{\pm}72\;mg/dL:\;57{\pm}53\;vs.\;27{\pm}12\;mg/dL$, P>0.05) compared with group II. Atorvastatin administration lowered the glomerular sclerosing index significantly(26.2% vs. 13.3%, P<0.05). Conclusion : Puromycin-induced glomerulosclerosis could be ameliorated by the reduction of hyperlipidemia with atorvastatin. This suggests that hyperlipidemia contributes to the pathogenesis of glomerulosclerosis. 목적 : PAN-induced nephrosis 쥐 모델에서 HMG-CoA reductase inhibitor로 작용하여 콜레스테롤을 낮추는 약제로 알려진 atorvastatin을 투여함으로써, 지질대사에 대한 효과와 지질대사의 변화가 쥐 모델의 신장 변화에 미치는 영향을 알아보고자 하였다. 대상 및 방법 : 수컷 Sprague-Dawley 흰쥐를 사용하여 대조군(I군), PAN 단독 투여군(II군), PAN과 atrovastatin 동시 투여군(III군) 3군으로 나누었으며, PAN은 체중 100 gm 당 2 mg을 첫 피하 주사한 후 1, 3, 5, 7, 9주에 반복하여 피하 주사하였으며, atorvastatin은 체중 100 gm당 5 mg을 물에 녹여 매일 경구 투여하였다. 실험 개시 후 11주에 24시간 소변과 혈액을 채취한 다음 신장을 적출 하였으며, 소변의 protein과 creatinine 그리고 혈청의 albumin, BUN, creatinine, lipid profiles를 측정하고, 신장의 형태학적 변화를 관찰하였다. 결과 : 혈청 총 콜레스테롤은 II군이 $291{\pm}173\;mg/dL$, III군이 $167{\pm}72\;mg/dL$, LDL은 II군이 $57{\pm}53\;mg/dL$, III군이 $27{\pm}12\;mg/dL$로 II군 보다 III군에서 감소하였으나 통계학적으로 유의하지는 않았다. 광학 현미경 검사상 사구체 경화의 빈도는 II군이 26.2%, III군이 13.3%로 II군보다 III군에서 적게 나타났다. 결론 : Atorvastatin을 puromycin과 같이 투여한 경우 총 콜레스테롤과 LDL을 낮추었으며 사구체 경화의 빈도도 감소시킨 것으로 보아 고지혈증이 사구체 경화성 변화에 중요한 원인 중의 하나로 생각된다.

Effects of atorvastatin on the induction of experimental cerebral aneurysm in a high lipid diet rat model

임정규,여인성,이진석,이형진,양지호,이일우 대한뇌혈관외과학회 2010 Journal of Cerebrovascular and Endovascular Neuros Vol.12 No.3

Objective : Previously, we reported that a high lipid diet significantly increases the induction rate of cerebral aneurysm (CA) formation in an experimentally induced CA rat model, suggesting that hypercholesterolemia with chronic inflammation leads to aneurysm formation. To elucidate the role of hypercholesterolemia in CA formation, experimentally induced CA was evaluated in rats fed a high lipid diet and treated with low and high doses of atorvastatin. Methods : Thirty-seven, 7-week-old male Sprague-Dawley rats underwent a CA induction procedure. The control animals (n = 11) were fed a normal diet, and the experimental animals (n = 26) were fed a diet containing high lipid content for 3 months. The experimental group comprised a high-dose atorvastatin group (20 mg/kg/day, n = 15) and low-dose atorvastatin group (1 mg/kg/day, n = 11). Three months after the operation, induction of CA formation in the three groups was analyzed. Results : Induced CA formation was 67%, 63%, and 36% in the control, high lipid/high atovastatin, and high lipid/low atovastatin group, respectively. The differences resulting from high-dose and low-dose atorvastatin were significant (Pearson k2, P = 0.028 and 0.029, respectively). Conclusions : A high lipid diet can significantly increase induction of CA formation. However, the lack of decreased induction in atorvastatin-treated animals suggests that high and low doses of atorvastatin do not inhibit the potential effects of hypercholesterolemia on CA formation. Further studies, such as those utilizing apolipoprotein E knockout mice, are necessary to elucidate the exact role of hypercholesterolemia in the pathophysiology of CA. (Kor J Cerebrovascular Surgery 12(3):196-201, 2010)

한국인 환자의 아토르바스타틴에 의한 근육통 발병률에 대한 단일 병원 전향연구: 스타틴근육통 임상지수의 적용

강규식,김병건 대한신경과학회 2022 대한신경과학회지 Vol.40 No.1

Background: Statin-induced myalgia is a common cause of discontinuation and a barrier that interferes with long-term treatment. The incidence of myalgia reported by previous atorvastatin trials in Korea ranged from 0.8% to 3.4%. This study assessed the incidence of myalgia after atorvastatin was administered to Korean patients with dyslipidemia. In addition, the Statin Myalgia Clinical Index (SMCI) was used to assess the likelihood that a patient’s myalgia was caused by atorvastatin. Methods: Dyslipidemic patients were eligible to participate if they were statin-naïve or treated with statins other than atorvastatin. Muscle complaints were assessed at the baseline, the 10-weeks visit and the final follow-up visit (16 weeks or later). The SMCI score was calculated if a patient developed myalgia, which was rated as probable, possible or unlikely related to the statin. Results: A total of 89 patients were analyzed. The atorvastatin doses ranged from 10 to 80 mg. Six (7%) patients reported new and unexplained muscle pain. Information on the timing of myalgia relative to stopping was unavailable in two patients. After excluding these two patients, three (3.4%) out of 87 patients were classified by the SMCI as having possible or probable atorvastatin-associated myalgia. Conclusions: In this study, the incidence of myalgia was higher than the incidences reported by the previous trials in Korea. However, the incidence of statin-associated myalgia assessed using SMCI was comparable to those of the trials. The SMCI may help diagnosis of statin-associated myalgia in clinical practice and optimize treatment for patients with myalgia.