(R)-Acenocoumarol
(Synonyms: (R)Acenocoumarin, (R)Nicoumalone) 目录号 : GC40552
Longer-lived enantiomer of the anticoagulant acenocoumarol
Cas No.:66556-77-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Acenocoumarol is a short-lived oral anti-coagulant, which, like warfarin, functions by inhibiting vitamin K epoxide reductase. It has higher intrinsic anticoagulant potency than warfarin and phenprocoumon, when evaluated in vitro. Acenocoumarol has a single chiral center that gives rise to two different enantiomeric forms. (R)-Acenocoumarol has a longer plasma elimination half-life (6.6 hours) and slower plasma clearance (1.9 L/hour), compared to the (S)-enantiomer (1.8 hours, 28.5 L/hour). The R-enantiomer is rapidly absorbed from the gastrointestinal tract with essentially complete oral bioavailability, whereas (S)-acenocoumarol undergoes extensive first-pass metabolism. Perhaps related to these pharmacokinetic characteristics, (R)-acenocoumarol is more potent in vivo as an anti-coagulant than the (S)-enantiomer. As the clearance of acenocoumarol is ~20-fold faster than that for warfarin, the plasma concentrations of acenocoumarol are substantially lower than those for warfarin in patients receiving long-term treatment.
| Cas No. | 66556-77-2 | SDF | |
| 别名 | (R)Acenocoumarin, (R)Nicoumalone | ||
| Canonical SMILES | O=C1C([C@@](CC(C)=O)([H])C2=CC=C([N+]([O-])=O)C=C2)=C(O)C3=CC=CC=C3O1 | ||
| 分子式 | C19H15NO6 | 分子量 | 353.3 |
| 溶解度 | DMF: 20 mg/ml,DMF:PBS (pH 7.2)(1:3): 0.25 mg/ml,DMSO: 10 mg/ml,Ethanol: 0.2 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 | 2.8305 mL | 14.1523 mL | 28.3046 mL |
| 5 mM | 0.5661 mL | 2.8305 mL | 5.6609 mL |
| 10 mM | 0.283 mL | 1.4152 mL | 2.8305 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。
Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3
Clin Pharmacol Ther 2001 Sep;70(3):292-8.PMID:11557918DOI:10.1067/mcp.2001.117936.
Objective: Our objective was to study the pharmacokinetics of R - and S -Acenocoumarol in a subject who was highly sensitive to the anticoagulant effect of acenocoumarol. The subject was found to be heterozygous for CYP2C9*3. Methods: The plasma pharmacokinetics of the acenocoumarol enantiomers was established after an oral dose of 8 mg of racemic acenocoumarol. Urine was collected to establish the formation clearance of the 6- and 7-hydroxy metabolites of R - and S -Acenocoumarol. Results: The pharmacokinetics of S -Acenocoumarol in this subject differed greatly (oral clearance, 6%-10%; half-life of elimination, 400%-500%) from the values of a [wt/wt] control and from population values. R -Acenocoumarol clearance was at the lower level of population values. The apparent formation clearances of the metabolites were low-approximately 10% of control activity for the hydroxylations (6- and 7-) of S -Acenocoumarol and for the 7-hydroxylation of R -Acenocoumarol. The rate of the 6-hydroxylation of R -Acenocoumarol was about 50% of control values. Conclusion: The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S -Acenocoumarol. As a result the first-pass effect of elimination is abolished and the maintenance time is increased. S -Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity.
Stereoselective interaction between piroxicam and acenocoumarol
Br J Clin Pharmacol 1996 Jun;41(6):525-30.PMID:8799517DOI:10.1046/j.1365-2125.1996.03558.x.
1. An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2. Eight healthy male volunteers received an oral dose of 4 mg rac-acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3. The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P < 0.05; AUC(0, 24 h)+47.2% (21.5), P < 0.005; and t1/2 +38.0% (34.5), P < 0.01. A concomitant decrease of CL/F was observed: -30.8% (10.0), P < 0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): + 15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: -9.8% (20.5). V/F remained unchanged for both enantiomers. 4. Piroxicam plasma AUC(0, 24 h) correlated closely with R- and S-acenocoumarol AUCs on day 1 (R = 0.901, P < 0.005 and R = 0.797, P < 0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol (R = 0.903, P < 0.001) and S-acenocoumarol (R = 0.711, P < 0.05). 5. Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.
Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes
Drug Metab Dispos 2000 Nov;28(11):1284-90.PMID:11038154doi
The oral anticoagulant acenocoumarol is given as a racemic mixture. The (S)-enantiomer is rapidly cleared and is the reason why only (R)-Acenocoumarol contributes to the pharmacological effect. The objective of the study was to establish the cytochrome P450 (CYP) enzymes catalyzing the hydroxylations of the acenocoumarol enantiomers. Of various cDNA-expressed human CYPs, only CYP2C9 hydroxylated (S)-acenocoumarol. Hydroxylation occurred at the 6-, 7-, and 8-position with equal K(m) values and a ratio of 0.9:1:0.1 for V(max). CYP2C9 also mediated the 6-, 7-, and 8-hydroxylations of (R)-Acenocoumarol with K(m) values three to four times and V(max) values one-sixth times those of (S)-acenocoumarol. (R)-Acenocoumarol was also metabolized by CYP1A2 (6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). In human liver microsomes one enzyme only catalyzed (S)-acenocoumarol hydroxylations with K(m) values < 1 microM. In most of the samples tested the 7-hydroxylation of (R)-Acenocoumarol was also catalyzed by one enzyme only. The 6-hydroxylation was catalyzed by at least two enzymes. Sulfaphenazole could completely inhibit in a competitive way the hydroxylations of (S)-acenocoumarol and the 7-hydroxylation of (R)-Acenocoumarol. The 6-hydroxylation of (R)-Acenocoumarol could be partially inhibited by sulfaphenazole, 40 to 50%, and by furafylline, 20 to 30%. Significant mutual correlations were obtained between the hydroxylations of (S)-acenocoumarol, the 7-hydroxylation of (R)-Acenocoumarol, the 7-hydroxylation of (S)-warfarin, and the methylhydroxylation of tolbutamide. The results demonstrate that (S)-acenocoumarol is hydroxylated by a single enzyme, namely CYP2C9. CYP2C9 is also the main enzyme in the 7-hydroxylation of (R)-Acenocoumarol. Other enzymes involved in (R)-Acenocoumarol hydroxylation reactions are CYP1A2 and CYP2C19. Drug interactions must be expected, particularly for drugs interfering with CYP2C9. Also, drugs interfering with CYP1A2 and CYP2C19 may potentiate acenocoumarol anticoagulant therapy.
Effect of aliskiren, an oral direct renin inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers
Curr Med Res Opin 2008 Sep;24(9):2449-56.PMID:18662494DOI:10.1185/03007990802285763.
Objective: Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. Methods: This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18-45) to receive either aliskiren 300 mg or placebo once daily on days 1-10 of each treatment period and a single dose of acenocoumarol 10 mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R(+)- and S(-)-Acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR). Results: Co-administration with aliskiren had no effect on exposure to R(+)-Acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R(+)-Acenocoumarol AUC(0-t) and C(max) were 1.08 and 1.04, respectively, with 90% CI within the range 0.80-1.25. Co-administration of aliskiren resulted in a 19% increase in S(-)-Acenocoumarol AUC(0-t) (GMR 1.19; 90% CI 0.92, 1.54) and a 9% increase in C(max) (GMR 1.09; 90% CI 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUC(PT), PT(max), AUC(INR) and INR(max)), with 90% CI within the range 0.97-1.05. Conclusion: Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.
No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics
Eur J Clin Pharmacol 1999 Jan;54(11):865-8.PMID:10027662DOI:10.1007/s002280050568.
Objective: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. Methods: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). Results: The median (range) areas under the concentration-time curve (AUC) for (R)-Acenocoumarol were 3458 (3035-7312) microg x h 1(-1) in the absence of and 3667 (2907-7741) microg x h 1(-1) in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381-853) microg x h 1(-1) and 612 (425-1241) microg x h 1(-1). The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-Acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics.