HKC proliferation is inhibited in vitro by lacidipine (0.01-100 μM; 24 h) in a concentration-dependent manner[1]. By controlling the caspase-3 pathway, lacidipine (0.01-100 μM; 24 h) shields HKCs from apoptosis brought on by ATP depletion and recovery[1].

In the apoE-deficient animal, lacedipine (0.3, 1.0, 3.0 mg/kg; po; once daily for 10 weeks) decreases plasma endothelin concentrations and exhibits anti-atherogenic properties[2].

Cell Proliferation Assay[1]
Cell Types: HKC cells
Tested Concentrations: 0.01-100 μM
Incubation Duration: 24 h
Experimental Results: demonstrated anti-proliferative activity in a concentration-dependent manner.

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Apoptosis Analysis[1]
Cell Types: HKC cells (renal ischemia reperfusion (I/R) model)
Tested Concentrations: 1, 10 μM
Incubation Duration: 24 h
Experimental Results: AA-induced HKC cells apoptosis, with proportion of early apoptotic cells of 1.47% and 0.30% for 1 and 10 μM dosage, respectively.

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Western Blot Analysis[1]
Cell Types: HKC cells (renal ischemia reperfusion (I/R) model)
Tested Concentrations: 1, 10 μM
Incubation Duration: 24 h (pretreat)
Experimental Results: diminished the expression of cyt c of injured cells following ATP depletion and recovery. Dramatically increased the expression of the Bcl-2 protein, but diminished the Bax protein.

Animal/Disease Models: Female C57BL/6 mice (Homozygous ; apoE-deficient; atherosclerosis model)[2].
Doses: 0.3, 1.0, 3.0 mg/kg
Route of Administration: po (oral gavage); single daily for 10 weeks.
Experimental Results: Induced a significant dose-dependent decrease in plasma endothelin levels. Dramatically decreased the mean lesion area in a dose-related manner by 10, 17 and 53% for 0.3, 1.0, 3.0 mg/kg, respectively.

Absorption, Distribution and Excretion
Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver.
Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine.

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Metabolism / Metabolites
Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity.

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Biological Half-Life
The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state.

Protein Binding
Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein.

[1]. Lacidipine attenuates apoptosis via a caspase-3 dependent pathway in human kidney cells. Cell Physiol Biochem. 2013;32(4):1040-9.

[2]. The calcium-channel blocker lacidipine reduces the development of atherosclerotic lesions in the apoE-deficient mouse. J Hypertens. 2000 Oct;18(10):1429-36.

Lacidipine is a cinnamate ester and a tert-butyl ester.
Lacidipine is a lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity. Due to its long duration of action, lacidipine does not lead to reflex tachycardia. It displays specificity in the vascular smooth muscle, where it acts as an antihypertensive agent to dilate peripheral arterioles and reduce blood pressure. Compared to other dihydropyridine calcium antagonists, lacidipine exhibits a greater antioxidant activity which may confer potentially beneficial antiatherosclerotic effects. Lacidipine is a highly lipophilic molecule that interacts with the biological membranes. Through radiotracer analysis, it was determined that lacidipine displays a high membrane partition coefficient leading to accumulation of the drug in the membrane and slow rate of membrane washout. When visualized by small-angle X-ray diffraction with angstrom resolution to examine its location within the membranes, lacidipine was found deep within the membrane's hydrocarbon core. These results may explain the long clinical half-life of lacidipine. In randomised, well-controlled trials, administration of daily single-dose lacidipine ranging from 2-6 mg demonstrated comparable antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor). It is available as once-daily oral tablets containing 2 or 4 mg of the active compound commonly marketed as Lacipil or Motens. It is not currently FDA-approved.

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Drug Indication
Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

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Mechanism of Action
By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques.

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Pharmacodynamics
acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers).

C26H33NO6

455.54

455.23

103890-78-4

Lacidipine-13C8;1261432-01-2

5311217

White to off-white solid powder

1.1±0.1 g/cm3

558.4±50.0 °C at 760 mmHg

174-175°C

291.5±30.1 °C

0.0±1.5 mmHg at 25°C

1.540

5.49

1

7

11

33

805

0

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

GKQPCPXONLDCMU-CCEZHUSRSA-N

InChI=1S/C26H33NO6/c1-8-31-24(29)21-16(3)27-17(4)22(25(30)32-9-2)23(21)19-13-11-10-12-18(19)14-15-20(28)33-26(5,6)7/h10-15,23,27H,8-9H2,1-7H3/b15-14+

diethyl 2,6-dimethyl-4-[2-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]phenyl]-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 (5.49 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 (5.49 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.)