 Chemical Structure.png)
Nifedipine (Adalat, Procardia, Bay-1040, BAY-a-1040; Cordipin, Corinfar, Bay 1040) is a dihydropyridine calcium channel blocker (CCB) with antihypertensive effects. It has been used to lower blood pressure and to treat angina, Raynaud's phenomenon, and premature labor. Nifedipine targets L-type voltage-sensitive calcium channels. Nifedipine is a vasodilator that is selective for inotropic over chronotropic cardiac effects. Nifedipine causes a significant concentration-dependent increase in eNOS protein expression by cultured human coronary artery endothelial cells. Nifedipine antagonizes L-type Ca+ channels found throughout the cardiovascular system, but also blocks Kv channels, which are members of the same supergene family.
Physicochemical Properties
| Molecular Formula | C17H18N2O6 | |
| Molecular Weight | 346.33 | |
| Exact Mass | 346.116 | |
| CAS # | 21829-25-4 | |
| Related CAS # |
|
|
| PubChem CID | 4485 | |
| Appearance | Yellow crystals | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 475.3±45.0 °C at 760 mmHg | |
| Melting Point | 171-175 °C | |
| Flash Point | 241.2±28.7 °C | |
| Vapour Pressure | 0.0±1.2 mmHg at 25°C | |
| Index of Refraction | 1.559 | |
| LogP | 2.97 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 25 | |
| Complexity | 608 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | 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 |
|
| InChi Key | HYIMSNHJOBLJNT-UHFFFAOYSA-N | |
| InChi Code | 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 | |
| Chemical Name | dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
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. |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
L-type calcium channels [1] |
| ln Vitro |
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]. 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] |
| ln Vivo |
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]. 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] |
| Cell Assay |
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] |
| Animal Protocol |
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 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] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Sublingual dosing leads to a Cmax of 10ng/mL, with a Tmax of 50min, and an AUC of 25ng\\h/mL. Oral dosing leads to a Cmax of 82ng/mL, with a Tmax of 28min, and an AUC of 152ng\\h/mL. Nifedipine is a Biopharmaceutics Classification System Class II drug, meaning it has low solubility and high intestinal permeability. It is almost completely absorbed in the gastrointestinal tract but has a bioavilability of 45-68%, partly due to first pass metabolism. Nifedipine is 60-80% recovered in the urine as inactive water soluble metabolites, and the rest is eliminated in the feces as metabolites. The steady state volume of distribution of nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. The total body clearance of nifedipine is 450-700mL/min. Approximately 90% of an oral dose of nifedipine is rapidly absorbed from the GI tract following oral administration of the drug as conventional capsules. Only about 45-75% of an oral dose as conventional capsules reaches systemic circulation as unchanged drug since nifedipine is metabolized on first pass through the liver. Peak serum concentrations usually are reached within 0.5-2 hours after oral administration as conventional capsules. Food appears to decrease the rate but not the extent of absorption of nifedipine as conventional capsules. Plasma drug concentrations rise at a gradual, controlled rate after a nifedipine extended-release tablet dose and reach a plateau at approximately six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24-hour dosing interval. About a four-fold higher fluctuation index (ratio of peak to trough plasma concentration) was observed with the conventional immediate-release nifedipine capsule at t.i.d. dosing than with once daily nifedipine extended-release tablet. At steady-state the bioavailability of the nifedipine extended-release tablet is 86% relative to immediate-release nifedipine capsules. Administration of the nifedipine extended-release tablet in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced GI retention time over prolonged periods (ie, short bowel syndrome), however, may influence the pharmacokinetic profile of the drug which could potentially result in lower plasma concentrations. The manufacturer states that relative oral bioavailability differs little if conventional nifedipine capsules are swallowed intact, bitten and swallowed, or bitten and held sublingually. However, some data indicate that the rate and extent of absorption of nifedipine following sublingual administration may be decreased substantially. Oral bioavailability of nifedipine may be increased up to twofold in patients with liver cirrhosis. For more Absorption, Distribution and Excretion (Complete) data for Nifedipine (10 total), please visit the HSDB record page. Metabolism / Metabolites Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydronifedipine. The drug is extensively metabolized in the liver (to highly water-soluble, inactive metabolites) by the cytochrome P-450 microsomal enzyme system, including CYP3A. Nifedipine has known human metabolites that include Oxidized nifedipine. Biological Half-Life The terminal elimination half life of nifedipine is approximately 2 hours. In patients with normal renal and hepatic function, the plasma half-life of nifedipine is about 2 hours when administered as conventional capsules, and about 7 hours when administered as extended-release tablets (Adalat CC). |
| Toxicity/Toxicokinetics |
Interactions Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro. Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased Cmax and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine. Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding Cmax values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered. Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered. In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril. For more Interactions (Complete) data for Nifedipine (22 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 Rat oral 1022 mg/kg LD50 Rat ip 230 mg/kg LD50 Mouse oral 310 mg/kg LD50 Mouse ip 185 mg/kg LD50 Rabbit oral 504 mg/kg Nifedipine combined with cyclosporine A induced gingival overgrowth in rats, which was characterized by increased epithelial thickness and expanded connective tissue. [1] |
| References |
[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 |
| Additional Infomation |
Therapeutic Uses Calcium Channel Blockers; Tocolytic Agents; Vasodilator Agents Nifedipine extended-release tablets are indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine extended-release may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, eg, where pain has a variable threshold on exertion or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta blockers. /Included in US product label/ Nifedipine extended-release tablets are indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents. /Included in US product label/ Nifedipine extended-release tablets (ADALAT CC) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. /Included in US product label/ Drug Warnings The National Heart, Lung, and Blood Institute (NHLBI) concluded from the apparent concordance of findings from observational studies in hypertensive patients and from randomized studies principally in acute myocardial infarction and unstable angina patients that it seems prudent and consistent with current evidence to recommend that short-acting nifedipine, especially at high doses, be used in the management of hypertension, angina, or myocardial infarction with great caution, if at all. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with an ACE inhibitor (lisinopril) or dihydropyridine-derivative calcium-channel blocker (amlodipine) revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal myocardial infarction among these therapies. Serious adverse reactions requiring discontinuance of nifedipine therapy or dosage adjustment are relatively rare. An increase in the frequency, intensity, and duration of angina, possibly resulting from hypotension, has occurred rarely during initiation of nifedipine therapy. Additional serious adverse effects including myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmia or conduction defects have reportedly occurred in 4%, 2%, and less than 0.5% of patients receiving conventional nifedipine capsules, respectively, but these have not been directly attributed to the drug. Rarely, patients, usually receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to those patients, owing to their fixed impedance to flow across the aortic valve. For more Drug Warnings (Complete) data for Nifedipine (32 total), please visit the HSDB record page. Pharmacodynamics Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction. Nifedipine (BAY-a-1040) is an L-type calcium channel blocker, and its combination with cyclosporine A can synergistically induce gingival overgrowth in rats [1] - The synergistic tocolytic effect of Nifedipine and ritodrine on human myometrium suggests potential clinical application in the prevention of preterm labor [2] - Nifedipine increases cellular iron content by up-regulating the expression of iron influx proteins DMT1 and TfR1, providing insights into its effect on iron metabolism [3] - Nifedipine inhibits the growth and virulence of Phytophthora capsici by blocking L-type calcium channels, indicating its potential as a botanical fungicide or lead compound for antifungal drug development [4] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8874 mL | 14.4371 mL | 28.8742 mL | |
| 5 mM | 0.5775 mL | 2.8874 mL | 5.7748 mL | |
| 10 mM | 0.2887 mL | 1.4437 mL | 2.8874 mL |