Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
It is completely absorbed via the gastrointestinal tract; however, due to extensive first-pass metabolism via the portal circulation, its systemic bioavailability is only 15%. Food does not affect its bioavailability. Although plasma concentrations of metabolites are high due to reduced urinary excretion, these metabolites are inactive. Animal studies have shown that felodipine can cross the blood-brain barrier and placenta. 10 L/kg 0.8 L/min [Young healthy subjects] Metabolism/Metabolites Primarily metabolized in the liver via cytochrome P450 3A4. Six metabolites without significant vasodilatory effects have been identified. Biological Half-Life 17.5–31.5 hours in hypertensive patients; 19.1–35.9 hours in elderly hypertensive patients; 8.5–19.7 hours in healthy volunteers.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Since there is currently no information regarding the use of felodipine during lactation, alternative medications are recommended. ◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding Rate
99%, primarily bound to albumin.

[1]. Calcium and calmodulin antagonists binding to calmodulin and relaxation of coronary segments. J Pharmacol Exp Ther. 1983;226(2):330-334.

[2]. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat Commun. 2019 Apr 18;10(1):1817.

[3]. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat Commun. 2019 Apr 18;10(1):1817.

Felodipine is a mixed (methyl, ethyl) diester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid. It is a calcium channel blocker that lowers blood pressure by reducing peripheral vascular resistance through highly selective action on arteriolar resistance smooth muscle. It is used to treat hypertension and angina. It has the effects of a calcium channel blocker, antihypertensive, vasodilator, and antiarrhythmic. It is a dihydropyridine, dichlorobenzene, ethyl ester, and methyl ester compound. Felodipine is a long-acting 1,4-dihydropyridine calcium channel blocker (CCB). It primarily acts on vascular smooth muscle cells through the inactive conformation of voltage-gated L-type calcium channels. Felodipine inhibits calcium-dependent muscle cell contraction and vasoconstriction by suppressing intracellular calcium ion influx into smooth muscle cells. Felodipine is currently the most potent calcium channel blocker (CCB), uniquely characterized by its fluorescent activity. In addition to binding to L-type calcium channels, felodipine can also bind to various calcium-binding proteins, competitively antagonizes mineralocorticoid receptors, inhibits calmodulin-dependent cyclic nucleotide phosphodiesterase activity, and blocks the influx of calcium ions through voltage-gated T-type calcium channels. Felodipine is used to treat mild to moderate essential hypertension. Felodipine is a dihydropyridine calcium channel blocker. Its mechanism of action is as a calcium channel antagonist. Felodipine is a second-generation calcium channel blocker and a commonly used antihypertensive drug. Felodipine treatment is associated with a low incidence of elevated serum enzymes, but there is no conclusive evidence that it is associated with clinically significant cases of acute liver injury. Felodipine is a dihydropyridine calcium channel blocker. Felodipine inhibits the influx of extracellular calcium ions into myocardial and vascular smooth muscle cells, leading to dilation of major coronary arteries and systemic arteries, and reducing myocardial contractility. This drug also inhibits the drug efflux pump P-glycoprotein, which is overexpressed in some multidrug-resistant tumors; therefore, felodipine may enhance the efficacy of certain antitumor drugs. (NCI04)
A dihydropyridine calcium channel blocker with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through highly selective action on the smooth muscle of small arteries.
See also: enalapril maleate; felodipine (ingredient).
Indications

For the treatment of mild to moderate essential hypertension.
FDA label
Mechanism of Action

Felodipine inhibits vasoconstriction by reducing arterial smooth muscle contractility by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes with nifedipine and other dihydropyridine calcium channel blockers (DHP CCBs) for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunits of myosin, a key step in muscle contraction. Signal amplification is achieved through calcium-induced release of calcium ions from the sarcoplasmic reticulum via renin receptors. Inhibition of initial calcium influx reduces the contractile activity of arterial smooth muscle cells, leading to vasodilation. The vasodilatory effect of felodipine results in an overall decrease in blood pressure. Felodipine can be used to treat mild to moderate essential hypertension.

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Pharmacodynamics
Felodipine belongs to the dihydropyridine calcium channel blockers (CCBs), the most widely used class of CCBs. At least five different types of calcium channels exist in the human body: L-type, N-type, P/Q-type, R-type, and T-type. It is generally believed that CCBs primarily act on L-type calcium channels, which are the main channels mediating muscle cell contraction; however, some studies have shown that felodipine can also bind to and inhibit T-type calcium channels. T-type calcium channels are most commonly found in neurons, pacemaker cells, and osteocytes. The pharmacological significance of T-type calcium channel blockade is unclear. Felodipine can also bind to calmodulin, inhibiting calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be small. Another study showed that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes in the cyclic nucleotide and calcium second messenger system. Felodipine can also act as a mineralocorticoid receptor antagonist by competitively binding to aldosterone and blocking aldosterone-induced recruitment of mineralocorticoid receptor coactivators. Felodipine can bind to troponin C isoforms in skeletal and cardiac muscle; troponin C is one of the key regulatory proteins of muscle contraction. Although felodipine can bind to a variety of endogenous molecules, its vasodilatory effect is still thought to be mainly achieved by inhibiting voltage-gated L-type calcium channels. Similar to other dihydropyridine calcium channel blockers (DHP CCBs), felodipine binds directly to inactivated calcium channels, stabilizing their inactivated conformation. Because arterial smooth muscle depolarization lasts longer than myocardial depolarization, inactivated calcium channels are more prevalent in smooth muscle cells. Selective splicing of the channel's α1 subunit confers additional arterial selectivity to felodipine. At therapeutic concentrations, felodipine has minimal effect on cardiomyocytes and conduction cells.

C18H14D5CL2NO4

389.28

388.1

1217744-87-0

3333

Typically exists as solid at room temperature

1.3±0.1 g/cm3

471.5±45.0 °C at 760 mmHg

239.0±28.7 °C

0.0±1.2 mmHg at 25°C

1.550

4.83

1

5

6

25

614

0

ClC1C(=CC=CC=1[C@@H]1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OC([2H])([2H])C([2H])([2H])[2H])Cl

RZTAMFZIAATZDJ-UHFFFAOYSA-N

InChI=1S/C18H19Cl2NO4/c1-5-25-18(23)14-10(3)21-9(2)13(17(22)24-4)15(14)11-7-6-8-12(19)16(11)20/h6-8,15,21H,5H2,1-4H3

5-O-ethyl 3-O-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-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.)