Absorption, Distribution and Excretion
Following a single, modified-release dose of 10mg barnidipine, the peak plasma concentration was approximately 0.48 µg/L and the area under the curve (AUC) was 2.85 µg/Lxh. The peak plasma concentrations are reached within 5 to 6 hours after oral administration of 20mg barnidipine. While the plasma concentrations of the drug may vary between individuals, the absolute bioavailability of the barnidipine is approximately 1.1% due to extensive first-pass hepatic metabolism. After repeated administration of 20mg barnidipine to healthy individuals, the concomitant intake of food did not have a statistically significant effect on the AUC, Cmax or half-life of the drug.
Barnidipine and its metabolites are metabolized into feces (60%), urine (40%) and breath (1%). Following a single dose administration of barnidipine ranging from 5 to 20mg in healthy volunteers, urinary excretion of unchanged drug was negligible (≤0.003% of an administered dose).
After administration of single oral doses of radiolabelled barnidipine in rats, levels of radioactivity were found to be higher in the kidney, liver and gastrointestinal tract than in plasma, whereas the brain showed the lowest level of radioactivity. The drug was also detectable in the breast milk.

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Metabolism / Metabolites
Barnidipine is expected to undergo hepatic metabolism. The primary metabolism of barnidipine involves the oxidation of the 1,4-dihydropyridine ring and hydrolysis of the methyl ester. Secondary metabolism involves N-debenzylization of the side chain, hydrolysis of the N-benzylpyrrolidine ester, and reduction of the nitro group. Both the primary and secondary metabolic pathways are mediated by the CYP3A isoenzyme family and the metabolites formed are pharmacologically inactive.
Barnidipine has known human metabolites that include 3-O-(1-Benzylpyrrolidin-3-yl) 5-O-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-O-methyl 5-O-pyrrolidin-3-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.

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Biological Half-Life
In a two-compartment analytical model, the median terminal elimination half life of barnidipine was 20 hours after repeated administration.

Protein Binding
In vitro binding of barnidipine with plasma proteins was between 92.4 and 98.9%, and was mainly with albumin. Barnidipine binds at the rate of 26-32% to human erythrocytes. In addition to serum albumin, barnidipine also binds to α1 acid glycoprotein and high density lipoproteins. To a much lesser extent, binding to γ-globulin takes place.

[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.
Barnidipine is a long-acting novel calcium antagonist that belongs to the dihydropyridine (DHP) group of calcium channel blockers. Used in the treatment of hypertension, barnidipine displays high affinity for the calcium channels of the smooth muscle cells in the vascular wall and selectivity against cardiovascular L-type calcium channels. Barnidipine contains two chiral centres thus can have four possible enantiomers. The active component is composed of a single optical isomer (*3'S, 4S* configuration), which is the most potent and longest-acting of the four enantiomers. Compared to several other calcium antagonists which are racemates, the barnidipine compound consisting of a single enantiomer may offer a high degree of pharmacological selectivity. According to a dose-ranging, multicentre, placebo-controlled, double-blind study in patients with mild to moderate hypertension, the antihypertensive response from barnidipine treatment was maintained after a 1-year and 2-year follow-up period in 91% of the patients who had an initial response to the drug. In two European multicentre randomized, double-blind trials, barnidipine was shown to possess equivalent antihypertensive efficacy to amlodipine and nitrendipine, but produced fewer class-specific side-effects. It also demonstrated clinical efficacy which is similar to that of atenolol, enalapril and hydrochlorothiazide. It is available in modified-release oral tablets under the brand name Vasexten to be taken once daily in the morning. Barnidipine has a gradual onset of action and is shown to be well tolerated in patients. It does not produce reflex tachycardia.

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Drug Indication
Indicated for the treatment of mild to moderate essential hypertension and management of chronic stable angina.

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Mechanism of Action
Barnidipine is a lipophilic 1,4-dihydropyridine calcium antagonist that is characterized by a slow onset of action and a strong and long-lasting binding to the L-type calcium channels. It displays high affinity for the channels expressed in the smooth muscle cells in the vascular wall. Its main mechanism of action arises from the reduction of peripheral vascular resistance secondary to its vasodilatory actions. Calcium ion influx via L-subtype ‘voltage-operated’ channels in the excitable membranes of the smooth muscle cells promotes the formation of calcium-dependent formation of cross-bridges between myosin and actin which are the two major contractile proteins that drive contraction. By blocking the L-type 'voltage-dependent' calcium channels, barnidipine selectively blocks the calcium ion influx in the smooth muscle cells and inhibits the activation of contractile proteins. It is suggested that barnidipine displays a high affinity to the inactivated state of the channel. Like other dihydropyridine calcium antagonists, barnidipine is predicted to interact with the alpha 1-C subunit of the L-type calcium channels. Alpha 1-C subunit of the channel is predicted to reside within the bilayer or channel pore at a location closer to the extracellular rather than the intracellular face of the membrane. Its lipophilicity is likely a reason why barnidipine displays a slow onset and long duration of action. Being a highly lipophilic molecule with an octanol/water partition coefficient of 2000, barnidipine is expected to accumulate in the cell membrane and consequently, gains access to its target receptor in a slow manner.

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Pharmacodynamics
Barnidipine reduces peripheral resistance and lowers blood pressure. The chronic use of the drug is not reported to lead to an increase in basic heart frequency. The antihypertensive effects of barnidipine are reported to remain during the entire 24-hour dose interval. Barnidipine does not exert any negative effect on serum lipids profile, glucose level or blood electrolytes.

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.)