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| ln Vivo |
A novel Ca2+ channel antagonist for spontaneously hypertensive rats is aranidipine (MPC-1304). Upon administering oral doses of 3 and 10 mg/kg of aradipine to spontaneously hypertensive rats (SHR), there was a significant increase in the Bmax value of specific [3H](+)-PN 200-110 binding to the myocardium in comparison to the control group. to reduce the values. In comparison to the control values, the Bmax values at 1 hour (3 mg/kg), 1 hour, and 6 hours (10 mg/kg) were significantly lower (47.7%, 48.9%, and 25.8%, respectively). The effect peaks after an hour and gradually wanes. The Bmax values following oral administration of alandipine at 6 hours (3 mg/kg) and 12 or 24 hours (10 mg/kg) did not show a significant difference from the control values, suggesting that the alandipine effect was no longer present. The myocardial [3H](+)-PN 200-110 binding's Kd value is unaffected by alandipine taken orally [1].
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| Animal Protocol |
Animals:** Male spontaneously hypertensive rats (SHR), aged 11-15 weeks, were used. They were fasted for 16 hours before drug administration. [1]
**Drug administration:** Aranidipine was suspended in 0.25% carboxymethyl cellulose sodium solution and administered orally at doses of 3 or 10 mg/kg in a volume of 5 mL/kg. Control animals received vehicle. [1] **Tissue collection for ex vivo binding:** At 1, 6, 12, and 24 hours after drug administration, SHR were killed by bleeding under light ether anesthesia. The myocardium and brain were perfused with 0.9% saline from the aorta, then removed for membrane preparation. [1] **Tissue collection for in vivo binding:** Aranidipine (3 mg/kg) was administered orally to SHR at 1, 6, and 12 hours before an intravenous injection of 555 kBq of [³H](+)-PN 200-110 into the femoral vein under light ether anesthesia. Rats were killed 10 minutes after the radioligand injection. Blood was collected, and myocardial, aortic, and cerebral cortical tissues were removed. [1] **Plasma concentration measurement:** Plasma was isolated by centrifugation from rat blood. The plasma concentration of aranidipine was determined by high-performance liquid chromatography (HPLC). [1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following administration, anadipine is rapidly absorbed from the gastrointestinal tract. After absorption, AUC and Cmax increase linearly in a dose-dependent manner, with the Cmax of anadipine reached approximately 3.8–4.8 hours and that of its metabolite M-1 reached approximately 4.8–6 hours. The bioavailability of anadipine in rats, dogs, and monkeys is approximately 48%, 41%, and 3%, respectively. One hour after administration, unmetabolized anadipine is detected in plasma but not in urine. Only trace amounts of the drug are detected in bile. These results indicate that the excretion of anadipine is primarily driven by metabolism rather than excretion. Including metabolites, 52–56% of the initial dose is excreted in urine, 34–45% in feces, and 3–4% in exhaled air. 59% of the administered dose is excreted in bile, of which 63% is reabsorbed. Metabolisms/Metabolites Eight anadipine metabolites were identified after oral administration. These metabolites are produced via ketone reduction, dihydropyridine epoxidation, and C-3 deesterification. Biological Half-Life The elimination half-lives of anadipine and M-1 metabolites are 1.1–1.2 hours and 2.7–3.5 hours, respectively. |
| Toxicity/Toxicokinetics |
Protein Binding
The plasma protein binding rate of aranidipine ranges from 84% to 95%. This binding rate is similar to that of the parent drug and its M-1 metabolite. Most of the drug binds to serum albumin, with a small amount binding to α1-acid glycoprotein. |
| References | |
| Additional Infomation |
Anadipine is an organic molecular entity. Anadipine is a novel dihydropyridine derivative that generates two active metabolites (M-1α and M-1β) with antihypertensive activity. It is a calcium channel blocker with the molecular formula methyl 2-oxopropyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate. It was developed by Maruko Pharmaceutical Co., Ltd., introduced by Taiho Pharmaceutical Co., Ltd., and launched in Japan in 1997. Indications: Anadipine has been used for the treatment of angina pectoris and hypertension for many years. Mechanism of Action: The high potential of anadipine is thought to be related to the additional calcium channel blocker activity of its metabolites. This mechanism is believed to be related to the ability of anadipine and its metabolites to dilate afferent and efferent arterioles. This action is achieved by inhibiting voltage-dependent calcium channels. Like all dihydropyridine drugs, anadipine's typical mechanism of action is based on inhibiting L-type calcium channels, thereby reducing calcium ion concentration and inducing smooth muscle relaxation. It is a selective α2-adrenergic receptor antagonist that inhibits vasoconstriction. Preclinical studies of anadipine and its two metabolites have shown that they increase femoral artery blood flow. Studies have shown that they have a potent and sustained vasodilatory effect. Anadipine and its metabolites inhibit calcium-induced contraction in isolated rabbit arteries. Studies have shown that anadipine has a stronger antihypertensive effect than other dihydropyridine drugs. Anadipine causes changes in renal blood flow, which may be due to its effect on α2-adrenergic receptor-mediated vasoconstriction.
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| Molecular Formula |
C19H20N2O7
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|---|---|
| Molecular Weight |
388.38
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| Exact Mass |
388.127
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| CAS # |
86780-90-7
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| PubChem CID |
2225
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.284 g/cm3
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| Boiling Point |
530ºC at 760 mmHg
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| Melting Point |
155°
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| Flash Point |
274.3ºC
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| Index of Refraction |
1.555
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| LogP |
2.986
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
28
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| Complexity |
748
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
NCUCGYYHUFIYNU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H20N2O7/c1-10(22)9-28-19(24)16-12(3)20-11(2)15(18(23)27-4)17(16)13-7-5-6-8-14(13)21(25)26/h5-8,17,20H,9H2,1-4H3
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| Chemical Name |
3-O-methyl 5-O-(2-oxopropyl) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
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| Synonyms |
Aranidipine MPC 1304 MPC-1304 MPC1304CCRIS 6724 CCRIS-6724 CCRIS6724
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~321.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5748 mL | 12.8740 mL | 25.7480 mL | |
| 5 mM | 0.5150 mL | 2.5748 mL | 5.1496 mL | |
| 10 mM | 0.2575 mL | 1.2874 mL | 2.5748 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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