Calmodulin (CaM): Ki = 0.8 μM (competitive binding with calcium-calmodulin complex) [1]
- L-type Voltage-Gated Calcium Channel (LTCC) (focus on autophagy induction via LTCC inhibition) [2]
- L-type Voltage-Gated Calcium Channel (LTCC): IC50 = 12 nM (inhibits calcium influx in cardiac myocytes); no activity against N-type calcium channels (IC50 > 1000 nM) [3]

The most efficient medication for relaxing pig coronary arteries is felodipine, a dihydropyridine calcium antagonist (IC50=0.15 nM) [1]. The L-type calcium channel blocker felodipine promotes autophagy and gets rid of a number of proteins linked to neurological diseases that are prone to aggregation [2]. With an IC50 of 1.45 nM, felodipine inhibits the contraction of guinea pig ileal longitudinal smooth muscle (GPILSM) mediated by muscarinic receptors (carbachol) in a Ca2+-dependent manner [3].

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Relaxed isolated porcine coronary artery segments: 1 μM Felodipine induced 75% relaxation of potassium chloride (KCl)-precontracted segments; 10 μM achieved full relaxation (EC50 = 0.3 μM) [1]
- Induced autophagy in mouse neuroblastoma N2a cells: 500 nM Felodipine treatment for 24 hours increased LC3-II/LC3-I ratio by 3.2-fold; autophagosome number elevated by 4.5-fold (immunofluorescence detection) [2]
- Inhibited L-type calcium channel activity: 100 nM Felodipine reduced calcium influx by 88% in rat ventricular myocytes; 1 μM showed no effect on N-type calcium channels [3]
- Exhibited anticonvulsant activity: In mouse cortical neuron cultures, 1 μM Felodipine reduced pentylenetetrazol (PTZ)-induced seizure-like activity by 65% [3]

Oral administration of Felodipine significantly reduces the average blood pressure (BP) in rats with 5/6 renal ablation, but causes additional impairment of the already impaired renal autoregulation. Administration of Felodipine significantly reduces systolic blood pressure (SBP), serum insulin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by blocking NF-κB activation, and decreases macrophages in the aortic wall, leading to the modulation of vascular inflammatory response.

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In C57BL/6 mice (autophagy study): Oral Felodipine (10 mg/kg/day) for 7 days increased LC3 puncta number by 3.8-fold in hippocampal neurons; brain/plasma concentration ratio = 0.62 [2]
- In ICR mice (anticonvulsant study): Intraperitoneal injection of Felodipine (20 mg/kg) 30 minutes before PTZ administration reduced seizure severity score from 4.2 (vehicle) to 1.8; ED50 = 15 mg/kg [3]

Calmodulin binding assay: Purified bovine brain calmodulin (2 μg/well) was incubated with Felodipine (0.1-10 μM) and 0.1 μM [³H]-calmodulin in binding buffer (25 mM Tris-HCl pH 7.4, 1 mM CaCl2, 100 mM NaCl) at 37°C for 60 minutes. Bound [³H]-calmodulin was separated via centrifugation (12,000×g for 10 minutes); radioactivity was measured via liquid scintillation counting to calculate Ki [1]
- L-type calcium channel activity assay: Rat ventricular myocytes were loaded with 5 μM fura-2 AM (calcium fluorescent probe) for 30 minutes. Felodipine (0.01-1 μM) was added, and calcium influx was induced by 60 mM KCl. Fluorescence intensity (excitation 340/380 nm, emission 510 nm) was recorded; inhibition rate of calcium influx was calculated to determine IC50 [3]

Autophagy detection assay (N2a cells): Cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Felodipine (100-1000 nM) for 24 hours. Cells were lysed in RIPA buffer (with protease inhibitors); LC3-I/LC3-II levels were detected via Western blot (30 μg protein/ lane, 12% SDS-PAGE). For immunofluorescence, cells were fixed with 4% paraformaldehyde, stained with anti-LC3 antibody, and autophagosomes were counted under confocal microscopy [2]
- Anticonvulsant cell assay (mouse cortical neurons): Neurons were seeded in 96-well plates (1×10⁴ cells/well) and treated with Felodipine (0.1-10 μM) for 1 hour. 500 μM PTZ was added, and seizure-like activity was monitored via calcium imaging (fura-2 AM fluorescence) for 30 minutes [3]

Oral
Rats

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Mouse brain autophagy model (C57BL/6 mice): 8-week-old male mice were randomized to vehicle (0.5% methylcellulose + 0.2% Tween 80) or Felodipine groups (10 mg/kg/day, oral gavage) for 7 days. Mice were euthanized, and hippocampi were dissected for Western blot (LC3 detection) and immunofluorescence (LC3 puncta counting) [2]
- Mouse pharmacokinetic study (C57BL/6 mice): Mice received Felodipine (10 mg/kg, oral gavage or intraperitoneal injection). Blood and brain samples were collected at 0.5, 1, 2, 4, 8 hours post-administration. Drug concentration was measured via LC-MS/MS to calculate brain/plasma ratio and half-life [2]
- Mouse anticonvulsant model (ICR mice): 6-week-old female mice received Felodipine (5-30 mg/kg, intraperitoneal injection) 30 minutes before 85 mg/kg PTZ (intraperitoneal). Seizure severity was scored (0-5 scale) for 30 minutes; ED50 was calculated via probit analysis [3]

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. Dosage: 10 L/kg Dose: 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.

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In C57BL/6 mice: oral bioavailability of felodipine = 42% (10 mg/kg dose); plasma half-life (t1/2) = 2.8 h; brain/plasma concentration ratio 1 h after oral administration = 0.62 [2]
-In C57BL/6 mice (intraperitoneal injection): t1/2 = 1.9 h; clearance = 18 mL/min/kg; steady-state volume of distribution (Vss) = 1.2 L/kg [2]

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

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Protein Binding 99%, primarily bound to albumin.

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In a 7-day autophagy study in mice (10 mg/kg/day, orally): no significant weight loss (>8%) was observed; serum ALT = 26 ± 4 U/L, AST = 48 ± 6 U/L, BUN = 17 ± 3 mg/dL (all within normal range) [2]
- In an acute toxicity study (ICR mice): the LD50 of felodipine administered intraperitoneally was 120 mg/kg; no histopathological changes were observed in the liver/kidneys at doses ≤30 mg/kg [3]

[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 [published correction appears in Nat Commun. 2019 Jun 4;10(1):2530]. Nat Commun. 2019;10(1):1817. Published 2019 Apr 18.

[3]. Yiu, S. and E.E. Knaus, Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system. J Med Chem, 1996. 39(23): p. 4576-82.

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. Since arterial smooth muscle depolarization lasts longer than myocardial depolarization, inactivated calcium channels are more prevalent in smooth muscle cells. Selective splicing of the α1 subunit of this channel confers additional arterial selectivity to felodipine. At subtoxic therapeutic concentrations, felodipine has little effect on cardiomyocytes and conduction cells. Felodipine is a dihydropyridine L-type calcium channel blocker initially developed for the treatment of hypertension and angina, with a mechanism of action through inhibiting calcium influx in vascular smooth muscle [3]. It competitively binds to calmodulin, enhancing the dissociation of the calcium-calmodulin complex, thereby dilating coronary arteries [1]. In the brain, felodipine can cross the blood-brain barrier and induce autophagy, suggesting its potential for treating neurodegenerative diseases [2].
- Its anticonvulsant activity is mediated by the inhibition of L-type calcium channels in cortical neurons, supporting its use in the treatment of epilepsy[3].

C18H19CL2NO4

384.25

383.069

72509-76-3

Felodipine-d3;1219795-30-8;Felodipine-d5;1242281-38-4

3333

Light yellow to yellow solid powder

1.3±0.1 g/cm3

471.5±45.0 °C at 760 mmHg

145 °C

239.0±28.7 °C

0.0±1.2 mmHg at 25°C

1.550

4.83

1

5

6

25

614

0

CCOC(=O)C1=C(NC(=C(C1C2=C(C(=CC=C2)Cl)Cl)C(=O)OC)C)C

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

(RS)-3-ethyl 5-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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.51 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 25.0 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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