Absorption, Distribution and Excretion
Following a single 10 mg dose of the extended-release barnidipine, peak plasma concentrations are approximately 0.48 µg/L, with an area under the curve (AUC) of 2.85 µg/L·h. Peak plasma concentrations are reached within 5 to 6 hours after an oral dose of 20 mg barnidipine. Although plasma concentrations may vary from person to person, the absolute bioavailability of barnidipine is approximately 1.1% due to extensive first-pass hepatic metabolism. In healthy subjects, repeated administration of 20 mg barnidipine with food had no statistically significant effect on the AUC, Cmax, or half-life. Barnidipine and its metabolites are primarily excreted in feces (60%), urine (40%), and exhalation (1%). In healthy volunteers, the amount of unchanged barnidipine excreted in urine after a single dose of 5 to 20 mg is negligible (≤0.003% of the administered dose).
In rats, after a single oral administration of radiolabeled barnidipine, radioactivity levels were found to be higher in the kidneys, liver, and gastrointestinal tract than in plasma, while the lowest radioactivity levels were observed in brain tissue. The drug was also detectable in breast milk.
Metabolism/Metabolites

Barnidipine is expected to be primarily metabolized in the liver. Primary metabolism of barnidipine involves the oxidation of the 1,4-dihydropyridine ring and the hydrolysis of the methyl ester. Secondary metabolism involves N-debenzylation of the side chain, hydrolysis of N-benzylpyrrolidone ester, and reduction of the nitro group. Both primary and secondary metabolic pathways of barnidipine are mediated by the CYP3A isoenzyme family, and the resulting metabolites have no pharmacological activity.
The known human metabolites of barnidipine include 3-O-(1-benzylpyrrolidone-3-yl)5-O-methyl-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid ester, 3-O-methyl-5-O-pyrrolidone-3-yl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid ester, and 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ester.

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Biological half-life
In a two-compartment analytical model, the median terminal elimination half-life of barnidipine after repeated dosing is 20 hours.

Protein Binding
In vitro experiments showed that barnidipine binds to plasma proteins at a rate of 92.4% to 98.9%, primarily albumin. Barnidipine binds to human erythrocytes at a rate of 26% to 32%. Besides serum albumin, barnidipine also binds to α1-acid glycoprotein and high-density lipoprotein. Its binding to γ-globulin is much lower.

[1]. Pharmacological profile of barnidipine: a single optical isomer dihydropyridine calcium antagonist. Blood Press Suppl. 1998;1:5-8.

[2]. Barnidipine. Drugs. 2001;61(7):989-96; discussion 997-8.

Barnidipine is a dihydropyridine compound. It is a novel, long-acting calcium channel blocker belonging to the dihydropyridine (DHP) class of calcium channel blockers. Barnidipine is used to treat hypertension, exhibiting high affinity for calcium channels in vascular smooth muscle cells and selectivity for L-type calcium channels in the cardiovascular system. Barnidipine contains two chiral centers, thus allowing for four possible enantiomers. Its active ingredient is composed of a single optical isomer (3'S, 4S configuration), which is the most potent and longest-lasting of the four enantiomers. Compared to some other racemic calcium channel blockers, the single enantiomer composition of barnidipine may exhibit higher pharmacological selectivity. A dose-range, multicenter, placebo-controlled, double-blind study in patients with mild to moderate hypertension showed that among patients who initially responded to barnidipine treatment, 91% maintained antihypertensive efficacy during the 1- and 2-year follow-up periods. In two European multicenter randomized double-blind trials, barnidipine demonstrated antihypertensive efficacy comparable to amlodipine and nifedipine, but with fewer side effects. Its clinical efficacy is also similar to atenolol, enalapril, and hydrochlorothiazide. Barnidipine is marketed as a sustained-release tablet under the brand name Vasexten, taken once daily in the morning. Barnidipine has a slow onset of action and is well tolerated by patients. It does not cause reflex tachycardia. Indications: Barnidipine is indicated for the treatment of mild to moderate essential hypertension and chronic stable angina. Mechanism of Action: Barnidipine is a lipophilic 1,4-dihydropyridine calcium channel antagonist characterized by a slow onset of action and strong binding affinity to L-type calcium channels, resulting in a long duration of action. It has a high affinity for calcium channels expressed by vascular smooth muscle cells. Its primary mechanism of action stems from its vasodilatory effect, thereby reducing peripheral vascular resistance. Calcium ions flow into L-shaped voltage-gated channels on the excitable membrane of smooth muscle cells, promoting the formation of calcium-dependent cross-bridges between myosin and actin, two major contractile proteins driving vasoconstriction. Barnidipine selectively inhibits calcium ion influx into smooth muscle cells by blocking L-shaped voltage-dependent calcium channels, thereby inhibiting the activation of contractile proteins. Studies have shown that barnidipine has a high affinity for the inactivated state of this channel. Similar to other dihydropyridine calcium antagonists, barnidipine is expected to interact with the α1C subunit of the L-shaped calcium channel. The α1C subunit of this channel is expected to be located within the bimembrane or channel pore, and more towards the extracellular side than the intracellular side. Its lipophilicity may be one of the reasons for barnidipine's slow onset and long duration of action. Barnidipine is a highly lipophilic molecule with an octanol/water partition coefficient of 2000, and is expected to accumulate on the cell membrane, thus binding slowly to the target receptor.

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Pharmacodynamics
Banidipine reduces peripheral resistance and lowers blood pressure. Long-term use of this drug has been reported not to cause an increase in baseline heart rate. The antihypertensive effect of barnidipine persists throughout the 24-hour dosing interval. Barnidipine has no adverse effects on blood lipids, blood glucose, or electrolyte levels.

C27H29N3O6

491.53566

491.205

104713-75-9

Barnidipine hydrochloride;104757-53-1;Barnidipine-d5;2771469-19-1

443869

Typically exists as solid at room temperature

1.3±0.1 g/cm3

614.5±55.0 °C at 760 mmHg

137-139°

325.4±31.5 °C

0.0±1.8 mmHg at 25°C

1.628

4.36

1

8

8

36

917

2

CC1=C([C@@H](C(=C(N1)C)C(=O)O[C@H]2CCN(C2)CC3=CC=CC=C3)C4=CC(=CC=C4)[N+](=O)[O-])C(=O)OC

VXMOONUMYLCFJD-DHLKQENFSA-N

InChI=1S/C27H29N3O6/c1-17-23(26(31)35-3)25(20-10-7-11-21(14-20)30(33)34)24(18(2)28-17)27(32)36-22-12-13-29(16-22)15-19-8-5-4-6-9-19/h4-11,14,22,25,28H,12-13,15-16H2,1-3H3/t22-,25-/m0/s1

5-O-[(3S)-1-benzylpyrrolidin-3-yl] 3-O-methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)