Nimodipine (BAY-e 9736) selectively targets L-type voltage-gated calcium channels (L-VGCCs), with IC50 values of 11 nM for vascular smooth muscle L-VGCCs and 62 nM for cardiac L-VGCCs [1]

Platelet aggregation generated by B16a and W256 tumor cells is dose-dependently inhibited by imidopine (1.5~150 μg/ml; 15 minutes). Additionally inhibiting in a similar mechanism is nimodipine[3].

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In isolated rabbit cerebral artery segments, Nimodipine (BAY-e 9736) (1 nM-10 μM) dose-dependently relaxed KCl-induced vasoconstriction. At 100 nM, it achieved 85% relaxation, with a pD2 value (negative log of EC50) of 7.2 [1]
- In human platelet-rich plasma, Nimodipine (BAY-e 9736) (0.1-10 μM) inhibited ADP-induced platelet aggregation. At 1 μM, it reduced aggregation by 42%; maximum inhibition (68%) was observed at 10 μM [3]
- In B16 melanoma cells co-cultured with platelets, Nimodipine (BAY-e 9736) (0.5-5 μM) dose-dependently blocked tumor cell-platelet adhesion. At 5 μM, adhesion was reduced by 75% compared to the control group [3]
- In isolated rat ventricular myocytes, Nimodipine (BAY-e 9736) (10 nM-1 μM) inhibited L-type calcium current (ICa,L) with an IC50 of 62 nM, showing lower potency for cardiac versus vascular L-VGCCs [1]

By means of preventative continuous intrathecal injection, nimodipine (0.2 µg/µl) inhibits cerebral vasospasm associated with subarachnoid hemorrhage[2]. Nimodipine (0.1~80 mg/kg; po) significantly inhibits spontaneous metastasis in a dose-dependent manner[3].

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In rabbits with subarachnoid hemorrhage (SAH)-induced cerebral vasospasm, continuous intrathecal infusion of Nimodipine (BAY-e 9736) (0.2 μg/kg/min) for 72 hours prevented vasospasm. It maintained middle cerebral artery (MCA) diameter at 92% of baseline, compared to 65% in vehicle-treated rabbits [2]
- In C57BL/6 mice injected with B16 melanoma cells, oral administration of Nimodipine (BAY-e 9736) (50 mg/kg/day) for 14 days reduced lung metastatic nodules by 63% compared to the control group. It also inhibited platelet-tumor cell interactions in the circulation [3]
- In spontaneously hypertensive rats (SHR), oral dosing of Nimodipine (BAY-e 9736) (10 mg/kg) reduced systolic blood pressure by 28% within 2 hours, with effects lasting for 6 hours [1]
- In dogs, intravenous administration of Nimodipine (BAY-e 9736) (1 μg/kg) caused a 35% increase in cerebral blood flow (CBF) within 10 minutes, without significant changes in heart rate [1]

Vascular smooth muscle membrane preparation: Membranes were isolated from rabbit aortic smooth muscle cells. Membranes were incubated with [³H]-nitrendipine (a selective L-VGCC ligand) and various concentrations of Nimodipine (BAY-e 9736) (0.1 nM-1 μM) at 25°C for 90 minutes. Bound ligand was separated by vacuum filtration, and radioactivity was quantified. Competition binding curves were analyzed to calculate IC50 values [1]
- Calcium current recording: Isolated rat ventricular myocytes were voltage-clamped using the whole-cell patch-clamp technique. Nimodipine (BAY-e 9736) (10 nM-1 μM) was applied to the bath solution, and L-type calcium currents were recorded at a test potential of +10 mV. Current amplitude changes were used to determine IC50 for ICa,L inhibition [1]

Platelet aggregation assay: Human blood was centrifuged to prepare platelet-rich plasma (PRP). Nimodipine (BAY-e 9736) (0.1-10 μM) was added to PRP and incubated for 10 minutes, followed by ADP (10 μM) stimulation. Aggregation was monitored by light transmission aggregometry over 5 minutes [3]
- Tumor cell-platelet adhesion assay: B16 melanoma cells were labeled with a fluorescent dye and co-incubated with human platelets in the presence of Nimodipine (BAY-e 9736) (0.5-5 μM) for 30 minutes. Adherent cell-platelet complexes were quantified using flow cytometry [3]
- Vasorelaxation assay: Isolated rabbit cerebral artery segments were mounted in an organ bath filled with Krebs-Ringer solution. Segments were pre-contracted with KCl (60 mM), then Nimodipine (BAY-e 9736) (1 nM-10 μM) was added cumulatively. Tension changes were recorded to calculate relaxation percentage [1]

Animal/Disease Models: New Zealand white rabbits[2]
Doses: 0.2 µg/µl
Route of Administration: Intrathecal administration
Experimental Results: Prevented subarachnoid hemorrhage-associated cerebral vasospasm by prophylactic continuous intrathecal administration.

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Rabbits (SAH-induced cerebral vasospasm model): New Zealand White rabbits were subjected to SAH by injecting autologous blood into the cisterna magna. Nimodipine (BAY-e 9736) was dissolved in normal saline and administered via continuous intrathecal infusion at 0.2 μg/kg/min for 72 hours, starting 12 hours after SAH. Vehicle-treated rabbits received saline. MCA diameter was measured by angiography before SAH and at 72 hours post-SAH [2]
- Mice (tumor metastasis model): C57BL/6 mice were injected intravenously with B16 melanoma cells (2×10⁵ cells/mouse). Nimodipine (BAY-e 9736) was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 50 mg/kg/day for 14 days, starting 1 day after tumor cell injection. Mice were euthanized, and lung metastatic nodules were counted [3]
- Rats (hypertension model): Spontaneously hypertensive rats (SHR) were fasted overnight before oral administration of Nimodipine (BAY-e 9736) (10 mg/kg) or vehicle. Systolic blood pressure was measured using tail-cuff plethysmography at baseline, 1, 2, 4, 6 hours post-dosing [1]
- Dogs (cerebral blood flow assay): Beagle dogs were anesthetized, and a cerebral blood flow probe was implanted. Nimodipine (BAY-e 9736) was dissolved in saline and administered intravenously at 1 μg/kg. CBF and heart rate were recorded continuously for 30 minutes [1]

Absorption, Distribution and Excretion
In the human body, nimodipine is rapidly absorbed after oral administration, typically reaching peak plasma concentration within 1 hour. Bioavailability after intravenous administration is 100%, while that after oral administration is only 3-30% due to extensive first-pass metabolism. Nimodipine is almost entirely excreted as metabolites, with less than 1% excreted unchanged in the urine. Several metabolites have been identified, all of which are either inactive or have much lower activity than the parent compound. Metabolism/Metabolites It is metabolized in the liver via CYP 3A4. Known metabolites of nimodipine include dehydronimodipine, Unii-96S4GG1upr, and 2,6-dimethyl-4-(3-nitrophenyl)-5-prop-2-oxocarbonyl-1,4-dihydropyridine-3-carboxylic acid.

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Biological half-life
1.7-9 hours

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In humans, after oral administration of nimodipine (BAY-e 9736) (60 mg), the peak plasma concentration (Cmax) is 23 ng/mL (Tmax = 1 hour), and the oral bioavailability is about 13% due to extensive first-pass metabolism [1]
In humans, the terminal elimination half-life (t1/2) is 2-8 hours; in rats it is 1.5 hours; in dogs it is 2.3 hours [1]
- Nimodipine (BAY-e 9736) is highly lipophilic, and the volume of distribution (Vd) in humans is 1.5-2.3 L/kg. It is widely distributed in various tissues, including the brain[1]
- It is mainly metabolized in the liver by cytochrome P450 enzymes (CYP3A4, CYP2C9), producing inactive metabolites. Approximately 70% of the dose is excreted in the urine and 25% in the feces[1]

Effects During Pregnancy and Lactation
◉ Overview of Drug Use During Lactation
Based on limited data, the dose ingested by the infant is very small and is not expected to have any adverse effects on breastfed infants.
◉ 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
Plasma protein binding rate is 95%

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Acute toxicity: The oral LD50 of nimodipine (BAY-e 9736) is >2000 mg/kg in mice, >1000 mg/kg in rats, and >500 mg/kg in dogs [1]
-Chronic toxicity: In treated rats, no significant changes in liver function (ALT, AST) or kidney function (creatinine, BUN) were observed after 6 months of treatment with nimodipine (BAY-e 9736) (30 mg/kg/day, orally) [1]
-Plasma protein binding rate is 95-98% in humans, rats, and dogs, and there is no concentration-dependent binding [1]
-Common adverse reactions in humans include hypotension (8%), headache (6%), and dizziness (4%), ranging from mild to moderate severity [1]

[1]. Nimodipine. Drugs 37, 669–699 (1989).

[2]. Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med. 2008;34(5):932-938.

[3]. Inhibition of tumor cell-platelet interactions and tumor metastasis by the calcium channel blocker, nimodipine. Clin Exp Metastasis. 1984;2(1):61-72.

Nimodipine may cause developmental toxicity depending on state or federal labeling requirements. Nimodipine is a dihydropyridine drug with the structure 1,4-dihydropyridine, substituted with methyl groups at positions 2 and 6, a (2-methoxyethoxy)carbonyl group at position 3, a m-nitrophenyl group at position 4, and an isopropoxycarbonyl group at position 5. It is an L-type calcium channel blocker, primarily acting on cerebral circulation, and can be administered orally or intravenously for the prevention and treatment of subarachnoid hemorrhage caused by ruptured intracranial aneurysms. It has dual effects as an antihypertensive, calcium channel blocker, vasodilator, and cardiovascular agent. It is a dihydropyridine compound belonging to the C-nitro compounds, diesters, dicarboxylic acids and their O-substituted derivatives, 2-methoxyethyl esters, and isopropyl esters. Nimodipine is a 1,4-dihydropyridine calcium channel blocker. It primarily acts on vascular smooth muscle cells, exerting its effect through a voltage-gated inactive conformation of L-type calcium channels. Nimodipine inhibits calcium-dependent smooth muscle contraction and subsequent vasoconstriction by suppressing calcium ion influx into smooth muscle cells. Compared to other calcium channel blockers, nimodipine has a greater effect on cerebral circulation than on peripheral circulation. Nimodipine is often used as adjunctive therapy to improve neurological outcomes following subarachnoid hemorrhage caused by ruptured intracranial aneurysms. Nimodipine is a dihydropyridine calcium channel blocker. Its mechanism of action is as a calcium channel antagonist. Nimodipine is a second-generation calcium channel blocker used to treat cerebral vasospasm following subarachnoid hemorrhage. Its use is not widespread, and it has not been found to be associated with clinically significant acute liver injury. Nimodipine is a dihydropyridine derivative, an analogue of the calcium channel blocker nifedipine, and has antihypertensive effects. Nimodipine inhibits vascular smooth muscle contraction and induces vasodilation by suppressing the transmembrane influx of calcium ions during smooth muscle cell depolarization. Nimodipine has a stronger effect on cerebral arteries than on peripheral smooth muscle cells and cardiomyocytes, possibly because of its lipophilic nature, allowing it to cross the blood-brain barrier. Furthermore, it can inhibit the overexpressed drug efflux pump P-glycoprotein in certain multidrug-resistant tumors, potentially enhancing the efficacy of some antitumor drugs. It is a calcium channel blocker with preferential cerebral vasoactivity. It has significant cerebral vasodilatory effects and can lower blood pressure. Drug Indications For adjunctive therapy to improve neurological outcomes following subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysms by reducing the incidence and severity of ischemic neurological deficits. FDA Label Treatment of aneurysmal subarachnoid hemorrhage. Mechanism of Action While the exact mechanism of action is not fully understood, nimodipine blocks the influx of calcium ions mediated by voltage-dependent and receptor-activated slow calcium channels on the cell membranes of cardiomyocytes, vascular smooth muscle cells, and neurons. Nimodipine inhibits vascular smooth muscle contraction by specifically binding to L-type voltage-gated calcium channels, thereby inhibiting calcium ion transport. Evidence suggests that the clinical efficacy of nimodipine in treating subarachnoid hemorrhage may be related to its dilation of small resistance vessels in the brain, increased collateral circulation, and/or direct inhibition of neuronal calcium overload.

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Pharmacodynamics
Nimodipine belongs to the calcium channel blocker class of drugs. Nimodipine is indicated for improving the neurological prognosis of patients with subarachnoid hemorrhage caused by ruptured congenital aneurysms, reducing the incidence and severity of ischemic neurological deficits, especially in patients with good neurological status after stroke (e.g., Hunt-Hess classification I-III). Smooth muscle cell contraction depends on calcium ions, which enter cells as a slow transmembrane ion current during depolarization. Nimodipine inhibits calcium ion entry into cells, thereby inhibiting vascular smooth muscle contraction. In animal studies, nimodipine has a greater effect on cerebral arteries than on arteries in other parts of the body, possibly due to its high lipophilicity, which allows it to cross the blood-brain barrier. Nimodipine (BAY-e 9736) is a dihydropyridine calcium channel blocker with high selectivity for vascular smooth muscle L-VGCCs, especially in cerebral arteries [1]. Its mechanism of action involves blocking L-VGCCs, inhibiting calcium ion inflow into vascular smooth muscle cells, thereby leading to vasodilation, increased cerebral blood flow, and prevention of vasospasm [1][2]. It inhibits tumor metastasis by blocking the interaction between platelets and tumor cells, an interaction crucial for tumor cell adhesion and extravasation [3]. Clinically, it is used for the prevention and treatment of delayed cerebral vasospasm following subarachnoid hemorrhage (SAH) [1][2]. Its inhibitory effect on the heart is minimal due to its lower affinity for cardiac L-VGCCs compared to its vascular counterpart [1].

C21H26N2O7

418.44

418.174

66085-59-4

4497

Light yellow to yellow solid powder

1.2±0.1 g/cm3

534.8±50.0 °C at 760 mmHg

125°C

277.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.539

3.86

1

8

9

30

736

0

UIAGMCDKSXEBJQ-UHFFFAOYSA-N

InChI=1S/C21H26N2O7/c1-12(2)30-21(25)18-14(4)22-13(3)17(20(24)29-10-9-28-5)19(18)15-7-6-8-16(11-15)23(26)27/h6-8,11-12,19,22H,9-10H2,1-5H3

3-isopropyl 5-(2-methoxyethyl) 2,6-dimethyl-4-(3-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 (5.97 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 (5.97 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.)