Atorvastatin lactone
(Synonyms: 阿托伐他汀内酯) 目录号 : GC42868
An active metabolite of atorvastatin
Cas No.:125995-03-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Atorvastatin lactone is a prodrug form of atorvastatin , an HMG-CoA reductase inhibitor used to lower blood cholesterol levels. The lactone hydrolyzes rapidly to the acid form of atorvastatin in human serum at room temperature. Atorvastatin lactone can also be formed in vivo from atorvastatin by certain uridine 5'-diphospho-glucuronosyltransferases. Like atorvastatin, the lactone inhibits P-glycoprotein in a concentration-dependent manner.
| Cas No. | 125995-03-1 | SDF | |
| 别名 | 阿托伐他汀内酯 | ||
| Canonical SMILES | O=C(C1=C(C(C)C)N(CC[C@H](C[C@@H](O)C2)OC2=O)C(C3=CC=C(F)C=C3)=C1C4=CC=CC=C4)NC5=CC=CC=C5 | ||
| 分子式 | C33H33FN2O4 | 分子量 | 540.6 |
| 溶解度 | DMF: 25 mg/ml,DMF:PBS (pH 7.2)(1:3): 0.25 mg/ml,DMSO: 15 mg/ml,Ethanol: 10 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8498 mL | 9.249 mL | 18.498 mL |
| 5 mM | 0.37 mL | 1.8498 mL | 3.6996 mL |
| 10 mM | 0.185 mL | 0.9249 mL | 1.8498 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Development of a population pharmacokinetic model for atorvastatin acid and its lactone metabolite
Clin Pharmacokinet 2010 Oct;49(10):693-702.PMID:20818835DOI:10.2165/11535980-000000000-00000.
Background and objectives: Atorvastatin lactone, a metabolite of the HMG-CoA reductase inhibitor (statin) atorvastatin acid, is believed to be myotoxic. Our objectives were to develop a population pharmacokinetic model for atorvastatin acid and its lactone metabolite and to identify patient characteristics that are predictive of variability in the pharmacokinetic parameters of the parent drug and its lactone metabolite. Subjects and methods: Twenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10 mg once daily for 7 days. Plasma samples taken on day 7 at 0 hours (predose) and 0.5, 1, 1.5, 2, 3, 5, 7, 9, 12, 22 and 24 hours post-dose were analysed for both atorvastatin acid and Atorvastatin lactone, using a validated liquid chromatography assay with tandem mass spectrometry, and the data were modelled using nonlinear mixed-effects modelling software (NONMEM). The influence of the patients' demographic characteristics, biochemical indices and pharmacogenomics was evaluated. Final model validation was carried out using a visual predictive check. Results: The pharmacokinetics of atorvastatin acid and Atorvastatin lactone were best described by two- and one-compartment models, respectively. The main pharmacokinetic parameters of atorvastatin acid (mean [relative standard error {RSE}]) for a subject with mean covariate values were the first-order absorption rate constant (3.5 h-1 fixed); oral clearance (504 L/h [29%]); apparent volume of the central compartment (3250 L [16.5%]); and apparent volume of the peripheral compartment (2170 L [9.3%]). The main pharmacokinetic parameters of Atorvastatin lactone (mean [RSE]) were the apparent clearance to atorvastatin acid (24 L/h [154%]); apparent total body clearance (116 L/h [9.5%]); and apparent volume of distribution (137 L [33.7%]). The value of aspartate transaminase was identified as a significant covariate for the apparent volume of the central compartment for atorvastatin acid and for the apparent total body clearance of Atorvastatin lactone, signifying the importance of liver function in atorvastatin pharmacokinetics. The visual predictive plots demonstrated that the model adequately described the pharmacokinetics of both species. Conclusion: A population pharmacokinetics model was developed and validated to describe atorvastatin acid and its lactone metabolite concentration-time data. This model may be useful for atorvastatin dose individualization or analysis of sparse data.
UGT1A1*28 is associated with decreased systemic exposure of Atorvastatin lactone
Mol Diagn Ther 2013 Aug;17(4):233-7.PMID:23580084DOI:10.1007/s40291-013-0031-x.
Background: Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of Atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma Atorvastatin lactone levels. Methods: DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing. Results: Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of Atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6 . Conclusion: The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite Atorvastatin lactone.
Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy
Clin Pharmacol Ther 2006 Jun;79(6):532-9.PMID:16765141DOI:10.1016/j.clpt.2006.02.014.
Background: The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls. Methods: A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls. Results: No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites Atorvastatin lactone (P<.01) and p-hydroxyatorvastatin (P<.01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups. Conclusions: This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.
Diabetes mellitus reduces the clearance of Atorvastatin lactone: results of a population pharmacokinetic analysis in renal transplant recipients and in vitro studies using human liver microsomes
Clin Pharmacokinet 2012 Sep 1;51(9):591-606.PMID:22775412DOI:10.2165/11632690-000000000-00000.
Background and objective: Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. Subjects and methods: A total of 312 plasma concentrations of atorvastatin acid and Atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis. Nonlinear mixed-effects modelling was employed to determine the population pharmacokinetic estimates for atorvastatin acid and Atorvastatin lactone. In addition, the biotransformation of these compounds was studied using human liver microsomal fractions obtained from 12 nondiabetic and 12 diabetic donors. Results: In diabetic patients, the plasma concentration of Atorvastatin lactone was significantly higher than that of atorvastatin acid throughout the 24-hour sampling period. The optimal population pharmacokinetic model for atorvastatin acid and Atorvastatin lactone consisted of a two- and one-compartment model, respectively, with interconversion between atorvastatin acid and Atorvastatin lactone. Parent drug was absorbed orally with a population estimate first-order absorption rate constant of 0.457 h(-1). The population estimates of apparent oral clearance (CL/F) of atorvastatin acid to Atorvastatin lactone, intercompartmental clearance (Q/F), apparent central compartment volume of distribution after oral administration (V(1)/F) and apparent peripheral compartment volume of distribution after oral administration (V(2)/F) for atorvastatin acid were 231 L/h, 315 L/h, 325 L and 4910 L, respectively. The population estimates of apparent total clearance of Atorvastatin lactone (CL(M)/F), apparent intercompartmental clearance of Atorvastatin lactone (Q(M)/F) and apparent volume of distribution of Atorvastatin lactone after oral administration (V(M)/F) were 85.4 L/h, 166 L/h and 249 L, respectively. The final covariate model indicated that the liver enzyme lactate dehydrogenase was related to CL/F and alanine aminotransferase (ALT) was related to Q/F. Importantly, diabetic patients have 3.56 times lower CL(M)/F than nondiabetic patients, indicating significantly lower clearance of Atorvastatin lactone in these patients. Moreover, in a multivariate population pharmacokinetics model, diabetes status was the only significant covariate predicting the values of the CL(M)/F. Correspondingly, the concentration of atorvastatin acid remaining in the microsomal incubation was not significantly different between nondiabetic and diabetic liver samples, whereas the concentration of Atorvastatin lactone was significantly higher in the samples from diabetic donors. In vitro studies, using recombinant enzymes, revealed that cytochrome P450 (CYP) 3A4 is the major CYP enzyme responsible for the biotransformation of Atorvastatin lactone. Conclusions: These studies provide compelling evidence that the clearance of Atorvastatin lactone is significantly reduced by diabetes, which leads to an increased concentration of this metabolite. This finding can be clinically valuable for diabetic transplant recipients who have additional co-morbidities and are on multiple medications.
Prediction of pharmacokinetic drug-drug interactions causing atorvastatin-induced rhabdomyolysis using physiologically based pharmacokinetic modelling
Biomed Pharmacother 2019 Nov;119:109416.PMID:31518878DOI:10.1016/j.biopha.2019.109416.
Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin's and its lactone's metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and Atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and Atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.