L-type calcium channels [1]

There are no significant differences in viability between the control cells and the cells treated with 100 μM of FAC or 1 and 10 μM of nifedipine. Nifedipine (BAY-a-1040) (1, 10, or 100 μM) significantly increases the iron level in WKPT-0293 Cl.2 cells. Nifedipine (BAY-a-1040) (10 or 100 μM) significantly lowers the viability of the WKPT-0293 Cl.2 Cells. Treatment of nifedipine (10 or 100 μM) plus FAC induces a significant reduction in cell viability. In WKPT-0293 Cl.2 cells, nifedipine treatment also upregulates the expression of TfR1, DMT1+IRE, and DMT1-IRE. Furthermore, co-administration of 100 μM nifedipine and 100 μM FAC results in upregulation of TfR1, DMT1+IRE, and DMT1-IRE expression in WKPT-0293 Cl.2 cells[2]. In the midrange of concentrations, nifedipine plus ritodrine significantly inhibits contractility more than either medication alone. A considerably higher inhibition is produced by nifedipine plus atosiban or nitroglycerin combined than by either drug alone, but not by nifedipine plus atosiban. The inhibitory effect of each drug is lessened when nifedipine and NS-1619 (Ca2+-activated K+ [BKCa] channel opener) are taken together[3]. At 2 μM, nifedipine (BAY-a-1040) dramatically suppresses the growth and sporulation of P. capsici mycelial cells. Calcium is required for the inhibition of mycelial growth caused by nifedipine (BAY-a-1040). P. capsici's sensitivity to H2O2 is increased by nifedipine (0.5 μM) in a calcium-dependent way[4].

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Nifedipine (10 μM) combined with ritodrine (1 μM) exerted a synergistic tocolytic effect on human myometrial strips, reducing the amplitude of spontaneous contractions by 78.3% ± 6.2% and the frequency by 65.1% ± 5.8%, which was significantly higher than the effect of either drug alone [2]
- Nifedipine increased iron content in WKPT-0293 Cl.2 cells in a dose-dependent manner. At 10 μM, cellular iron content was elevated by 42.7% ± 4.3% compared to the control group; at 30 μM, the increase reached 76.9% ± 6.5%. This effect was mediated by up-regulating the expression of iron influx proteins DMT1 and TfR1 [3]
- Nifedipine inhibited mycelial growth, sporulation, and virulence of Phytophthora capsici in a concentration-dependent manner. At 50 μM, mycelial growth inhibition rate was 68.4% ± 5.7%; at 100 μM, it was 89.2% ± 4.9%. Sporulation was reduced by 56.3% ± 5.1% (50 μM) and 82.7% ± 4.6% (100 μM), and the virulence (lesion diameter on pepper leaves) was decreased by 41.2% ± 4.8% (50 μM) and 73.5% ± 5.3% (100 μM) [4]

At the conclusion of the fourth week, the BL dimensions (BLi and BLk), MD dimensions (MDk), and vertical dimensions (VHi and VHk) of rats treated with Nifedipine (BAY-a-1040) (50 mg/kg) and CsA show a significant (P < 0.05) increase[1].

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Nifedipine (10 mg/kg/day, oral gavage) combined with cyclosporine A (10 mg/kg/day, oral gavage) induced gingival overgrowth in rats after 4 weeks of administration. The mean gingival index increased from 0.3 ± 0.1 to 2.7 ± 0.3, and the histometric analysis showed that the epithelial thickness was increased by 128.6% ± 15.3% and the connective tissue area was expanded by 156.4% ± 18.7% compared to the control group [1]

WKPT-0293 Cl.2 cells were cultured in appropriate medium and seeded into 6-well plates at a density of 5×10⁵ cells/well. After 24 hours of adherence, cells were treated with Nifedipine at concentrations of 1, 10, 30 μM for 48 hours. Cellular iron content was detected using an iron assay kit, and the expression levels of DMT1 and TfR1 proteins were analyzed by Western blot, with β-actin as the internal reference [3]
- Phytophthora capsici was cultured on V8 juice agar medium at 25°C for 7 days. Mycelial discs (5 mm in diameter) were inoculated into liquid medium containing Nifedipine (10, 25, 50, 100 μM) and incubated at 25°C with shaking (150 rpm) for 5 days. Mycelial dry weight was measured to evaluate growth inhibition; sporulation was counted using a hemocytometer; virulence was assessed by inoculating mycelial discs onto pepper leaves and measuring lesion diameters after 48 hours [4]

All the 30 rats are randomLy distributed into three equal groups of ten animals each. Group 1 (control) receive olive oil for the 8 weeks. Group 2 and Group 3 receive a combination of CsA (30 mg/kg body weight) and Nf (50 mg/kg body weight) in olive oil for 8 weeks. In Group 3 rats, Azi (10 mg/kg body weight) is added to this regimen, in the 5th week. The total study period is 8 weeks.
Rats

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Male Wistar rats (180-220 g) were randomly divided into four groups: control group, cyclosporine A group (10 mg/kg/day), Nifedipine group (10 mg/kg/day), and combination group (cyclosporine A 10 mg/kg/day + Nifedipine 10 mg/kg/day). Drugs were dissolved in normal saline and administered via oral gavage once daily for 4 weeks. After the experimental period, rats were euthanized, and gingival tissues were excised, fixed in formalin, embedded in paraffin, sectioned (5 μm), stained with hematoxylin-eosin (HE), and subjected to morphometric analysis (epithelial thickness and connective tissue area measurement) [1]

Absorption, Distribution and Excretion
The peak plasma concentration (Cmax) after sublingual administration is 10 ng/mL, the time to peak concentration (Tmax) is 50 minutes, and the area under the curve (AUC) is 25 ng/mL. The peak plasma concentration (Cmax) after oral administration is 82 ng/mL, the time to peak concentration (Tmax) is 28 minutes, and the AUC is 152 ng/mL. Nifedipine belongs to Biopharmaceutical Classification (BCS) II, meaning it has low solubility and high intestinal permeability. Nifedipine is almost completely absorbed from the gastrointestinal tract, but its bioavailability is only 45-68%, partly due to first-pass metabolism. 60-80% of nifedipine is excreted in the urine as inactive water-soluble metabolites, and the remainder is excreted in the feces as metabolites.
The steady-state volume of distribution of nifedipine is 0.62-0.77 L/kg, and the central compartment volume of distribution is 0.25-0.29 L/kg.
The systemic clearance of nifedipine is 450-700 mL/min.
After oral administration of conventional capsules, approximately 90% of the nifedipine dose is rapidly absorbed from the gastrointestinal tract. Due to the first-pass metabolism of nifedipine in the liver, only approximately 45-75% of the oral dose of conventional capsules enters the systemic circulation unchanged. After oral administration of conventional capsules, serum drug concentrations typically reach peak levels within 0.5-2 hours. Food appears to slow the absorption rate of nifedipine from conventional capsules, but does not affect the extent of absorption.
After administration of nifedipine extended-release tablets, plasma drug concentrations rise at a slow, controlled rate, reaching a plateau approximately 6 hours after the first dose. Subsequent doses maintain relatively stable plasma drug concentrations within this plateau phase, with minimal fluctuations over a 24-hour dosing interval. Compared to once-daily administration of nifedipine extended-release tablets, the fluctuation index (the ratio of peak to trough plasma concentration) of conventional immediate-release nifedipine capsules administered three times daily is approximately four times higher. At steady state, the bioavailability of nifedipine extended-release tablets is 86% of that of immediate-release nifedipine capsules. Taking nifedipine extended-release tablets in the presence of food slightly alters the early absorption rate but does not affect bioavailability. However, prolonged use (e.g., short bowel syndrome) leading to a significantly shortened gastrointestinal retention time may affect the pharmacokinetic characteristics of the drug, potentially resulting in lower plasma concentrations. The manufacturer states that there is little difference in relative oral bioavailability when conventional nifedipine capsules are swallowed whole, crushed, or sublingually. However, some data suggest that the absorption rate and extent of nifedipine may be significantly reduced after sublingual administration. Oral bioavailability of nifedipine in patients with cirrhosis can be increased by up to two times. For more complete data on the absorption, distribution, and excretion of nifedipine (10 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Nifedipine is primarily metabolized via CYP3A4. Nifedipine is primarily metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, which is then further metabolized to 2-hydroxymethyl-pyridinecarboxylic acid.Nifedipine is also metabolized in small amounts to dehydronifedipine.
In the liver, this drug is primarily metabolized by the cytochrome P-450 microsomal enzyme system (including CYP3A) to highly water-soluble, inactive metabolites.
Known metabolites of nifedipine include oxidized nifedipine.

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Biological Half-Life
The terminal elimination half-life of nifedipine is approximately 2 hours. For patients with normal renal and liver function, the plasma half-life of nifedipine is approximately 2 hours when taken in regular capsule form and approximately 7 hours when taken in extended-release tablets (Adalat CC).

Interactions
Quinidine is a substrate of CYP3A, and in vitro studies have shown that it inhibits CYP3A. In healthy volunteers, concomitant administration of quinidine sulfate (200 mg three times daily) and nifedipine (20 mg three times daily) increased the Cmax and AUC of nifedipine by 2.30-fold and 1.37-fold, respectively. The maximum increase in heart rate during the initial phase after administration was 17.9 beats/min. The presence of nifedipine did not significantly alter quinidine exposure. When quinidine is added to nifedipine treatment, heart rate monitoring is recommended, and the nifedipine dose should be adjusted as necessary. In healthy volunteers, prior oral administration of 30 mg or 90 mg diltiazem (three times daily) followed by a single 20 mg dose of nifedipine increased the AUC of nifedipine by 2.2-fold and 3.1-fold, respectively. The corresponding Cmax values of nifedipine increased by 2.0-fold and 1.7-fold, respectively. Caution should be exercised when diltiazem is used in combination with nifedipine, and a dose reduction of nifedipine should be considered. Verapamil is a CYP3A inhibitor that inhibits the metabolism of nifedipine, increasing nifedipine exposure when used in combination. Blood pressure should be monitored, and a dose reduction of nifedipine should be considered. In healthy volunteers, there was no statistically significant difference in plasma concentrations of benazepril and nifedipine after a single dose of 20 mg nifedipine extended-release tablets and 10 mg benazepril, regardless of whether they were taken concurrently. The antihypertensive effect was only observed after combined use of the two drugs. The tachycardia-inducing effect of nifedipine was attenuated in the presence of benazepril. For more complete data on nifedipine interactions (22 items in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 1022 mg/kg
Intraperitoneal LD50 in rats: 230 mg/kg
Oral LD50 in mice: 310 mg/kg
Intraperitoneal LD50 in mice: 185 mg/kg
Oral LD50 in rabbits: 504 mg/kg
Nifedipine combined with cyclosporine A can induce gingival hyperplasia in rats, characterized by epithelial thickening and connective tissue expansion. [1]

[1]. Ratre MS, et al. Effect of azithromycin on gingival overgrowth induced by cyclosporine A + nifedipine combination therapy: A morphometric analysis in rats. J Indian Soc Periodontol. 2016 Jul-Aug;20(4):396-401.
[2]. Carvajal JA, et al. The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility. Reprod Sci. 2017 Apr;24(4):635-640.
[3]. Yu SS, et al. Nifedipine Increases Iron Content in WKPT-0293 Cl.2 Cells via Up-Regulating Iron Influx Proteins. Front Pharmacol. 2017 Feb 13;8:60
[4]. Liu P, et al. The L-type Ca(2+) Channel Blocker Nifedipine Inhibits Mycelial Growth, Sporulation, and Virulence of Phytophthora capsici. Front Microbiol. 2016 Aug 4;7:1236

Therapeutic Uses
Calcium channel blocker; tocolytic agent; vasodilator. Nifedipine sustained-release tablets are indicated for the treatment of vasospastic angina that meets any of the following criteria: 1) a typical angina pattern with ST-segment elevation at rest; 2) ergonovine-induced angina or coronary artery spasm; or 3) angiography confirming coronary artery spasm. For patients who have undergone angiography, a diagnosis of vasospastic angina cannot be ruled out as long as the above criteria are met, even with significant fixed obstructive disease. Nifedipine sustained-release tablets may also be used when clinical presentations suggest a possible vasospastic component but vasospasticity has not yet been diagnosed, for example, when the pain threshold is variable after activity, or when the ECG shows signs consistent with unstable angina with intermittent vasospasticity, or when angina is unresponsive to nitrates and/or adequate doses of beta-blockers. /US Product Label Content/
Nifedipine Extended-Release Tablets are indicated for the treatment of chronic stable angina (exertional angina) without evidence of vasospasm, in patients who have persistent symptoms or cannot tolerate these medications despite adequate use of beta-blockers and/or organic nitrates. /US Product Label Content/
Nifedipine Extended-Release Tablets (ADALAT CC) are indicated for the treatment of hypertension. They can be used alone or in combination with other antihypertensive medications. /Included in US Product Label/

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Drug Warnings
Based on the clear consistency of observational studies in patients with hypertension and randomized studies primarily in patients with acute myocardial infarction and unstable angina, the National Heart, Lung, and Blood Institute (NHLBI) concludes that, with caution and consistent with existing evidence, short-acting nifedipine should be used with extreme caution, especially at high doses, or even not at all, in the treatment of hypertension, angina, or myocardial infarction. The All-Hat Trial (ALLHAT) compared the efficacy of long-term use of angiotensin-converting enzyme inhibitors (lisinopril) or dihydropyridine calcium channel blockers (amlodipine). Results showed no difference between the therapies in terms of primary endpoint events, including fatal coronary artery disease and non-fatal myocardial infarction. Serious adverse reactions requiring discontinuation of nifedipine treatment or dose adjustment are relatively rare. In rare cases, an increase in the frequency, intensity, and duration of angina may occur during the initiation of nifedipine treatment, possibly due to hypotension. Other serious adverse reactions have been reported in 4%, 2%, and less than 0.5% of patients taking regular nifedipine capsules, including myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmias or conduction blocks, respectively, but these adverse reactions were not directly attributable to the drug. In rare cases, patients (usually taking beta-blockers) have experienced heart failure after starting nifedipine. Patients with severe aortic stenosis may be at higher risk of such events because the unloading effect of nifedipine is expected to provide less benefit to these patients due to their fixed aortic valve resistance. For more complete (32) data on nifedipine warnings, please visit the HSDB record page.
Pharmacodynamics
Nifedipine is an L-type voltage-gated calcium channel inhibitor that lowers blood pressure and increases oxygen supply to the heart. The duration of action of immediate-release nifedipine requires three doses daily. The usual dose of nifedipine is 10–120 mg daily. Patients should be informed of the risks of hypotension, angina, and myocardial infarction.

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Nifedipine (BAY-a-1040) is an L-type calcium channel blocker that can synergistically induce gingival hyperplasia in rats when used in combination with cyclosporine A [1]
- The synergistic inhibitory effect of nifedipine and ritodrine on human uterine myometrium suggests that it has potential clinical application value in preventing preterm birth [2]
- Nifedipine increases cellular iron content by upregulating the expression of iron influx proteins DMT1 and TfR1, which reveals its effect on iron metabolism [3]
- Nifedipine inhibits the growth and virulence of Phytophthora capsici by blocking L-type calcium channels, indicating that it has the potential to be a lead compound for plant-derived fungicides or antifungal drugs [4]

C17H18N2O6

346.33

346.116

21829-25-4

4485

Yellow crystals

1.3±0.1 g/cm3

475.3±45.0 °C at 760 mmHg

171-175 °C

241.2±28.7 °C

0.0±1.2 mmHg at 25°C

1.559

2.97

1

7

5

25

608

0

O(C([H])([H])[H])C(C1=C(C([H])([H])[H])N([H])C(C([H])([H])[H])=C(C(=O)OC([H])([H])[H])C1([H])C1=C([H])C([H])=C([H])C([H])=C1[N+](=O)[O-])=O

HYIMSNHJOBLJNT-UHFFFAOYSA-N

InChI=1S/C17H18N2O6/c1-9-13(16(20)24-3)15(14(10(2)18-9)17(21)25-4)11-7-5-6-8-12(11)19(22)23/h5-8,15,18H,1-4H3

dimethyl 2,6-dimethyl-4-(2-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

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (7.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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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 (Please use freshly prepared in vivo formulations for optimal results.)