Calcium channel; Permeability-glycoprotein (P-gp); CYP3A4[1]

EverFluor FL Verapamil (EFV) 以浓度依赖性方式抑制 TR-iBRB2 细胞，而 Verapamil 以浓度抑制方式抑制 TR-iBRB2 细胞，IC50 为 98.0 μM [4]。

房颤时，维拉帕米（面部）可用于控制房室结反应，避免房室折返性心动过速[2]。将维拉帕米静脉注射到前胸部区域的股静脉中。冠状动脉闭合后 45 分钟内，维拉帕米（1 mg/kg）可显着降低室性心律失常的发生率，例如室性心动过速（VT）、心室颤动（VF）和室性早搏（PVC）。缺血性心脏导致总体心律失常评分显着增加。给予 1 mg/kg 维拉帕米可有效抑制心血管诱发的心律失常总体评分的上升[5]。

方法：采用EverFluor FL维拉帕米（EFV）作为维拉帕米的荧光探针，通过大鼠颈总动脉输注研究其在BRB中的转运。分别用TR-iBRB2细胞和RPE-J细胞研究了EFV在内外BRB的转运。 结果：在细胞不可渗透化合物的弱信号期间，视网膜组织中检测到EFV信号。在TR-iBRB2细胞中，EFV的定位不同于溶酶体运动剂LysoTracker®Red的定位，并且不会因NH4Cl的急性处理而改变。在RPE-J细胞中，部分观察到EFV的点状分布，经NH4Cl急性处理后，这种分布有所减少。TR-iBRB2细胞对EFV的摄取是温度依赖性的，与膜电位和pH无关，NH4Cl处理显著降低了EFV的吸收，而不同的细胞外pH和V-ATP酶抑制剂没有显著影响。TR-iBRB2细胞对EFV的摄取被阳离子药物抑制，维拉帕米以浓度依赖的方式抑制，IC50为98.0μM。[4]

维拉帕米的抗心律失常作用是在人们意识到它是一种钙离子拮抗剂之前观察到的。静脉注射维拉帕米在终止阵发性往复式房室心动过速方面非常有效，无论是与预激有关还是仅涉及房室结。它持续减缓和规范房颤患者的心室反应，通常会增加房扑患者的房室结传导阻滞程度，尽管偶尔会导致窦性心律的恢复。口服可用于预防房室折返性心动过速，也可用于调节房颤患者的房室结反应。室性心动过速的有利反应是罕见的，然后在特定的良性品种中可见。维拉帕米是终止阵发性室上性心动过速的首选药物[2]。

The present study was to test the hypothesis that anti-arrhythmic properties of verapamil may be accompanied by preserving connexin43 (Cx43) protein via calcium influx inhibition. In an in vivo study, myocardial ischemic arrhythmia was induced by occlusion of the left anterior descending (LAD) coronary artery for 45 min in Sprague-Dawley rats. Verapamil, a calcium channel antagonist, was injected i.v. into a femoral vein prior to ischemia. Effects of verapamil on arrhythmias induced by Bay K8644 (a calcium channel agonist) were also determined. In an ex vivo study, the isolated heart underwent an initial 10 min of baseline normal perfusion and was subjected to high calcium perfusion in the absence or presence of verapamil. Cardiac arrhythmia was measured by electrocardiogram (ECG) and Cx43 protein was determined by immunohistochemistry and western blotting. Administration of verapamil prior to myocardial ischemia significantly reduced the incidence of ventricular arrhythmias and total arrhythmia scores, with the reductions in heat rate, mean arterial pressure and left ventricular systolic pressure. Verapamil also inhibited arrhythmias induced by Bay K8644 and high calcium perfusion. Effect of verapamil on ischemic arrhythmia scores was abolished by heptanol, a Cx43 protein uncoupler and Gap 26, a Cx43 channels inhibitor. Immunohistochemistry data showed that ischemia-induced redistribution and reduced immunostaining of Cx43 were prevented by verapamil. In addition, diminished expression of Cx43 protein determined by western blotting was observed following myocardial ischemia in vivo or following high calcium perfusion ex vivo and was preserved after verapamil administration. Our data suggest that verapamil may confer an anti-arrhythmic effect via calcium influx inhibition, inhibition of oxygen consumption and accompanied by preservation of Cx43 protein[5].

Absorption, Distribution and Excretion
More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. Tmax) between 1-2 hours following administration, whereas sustained-release formulations tend to have a Tmax between 6 - 11 hours. AUC and Cmax values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC0-24h and Cmax values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state.
Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug.
Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer.
Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil.
/MILK/ Breast milk: Verapamil may appear in breast milk.
/MILK/ Verapamil is excreted into breast milk. A daily dose of 240 mg produced milk levels that were approx 23% of maternal serum. Serum levels in the infant were 2.1 ng/mL but could not be detected (<1 ng/mL) 38 hr after treatment was stopped. ... In a second case, a mother was treated with 80 mg 3 times/day for hypertension for 4 wk prior to the determination of serum & milk concns. Steady-state concentrations of verapamil and the metabolite, norverapamil, in milk were 25.8 and 8.8 ng/mL, respectively. These values were 60% and 16% of the concns in plasma. The investigators estimated that the breast-fed child received <0.01% of the mother's dose. Neither verapamil nor the metabolite could be detected in the plasma of the child.
The pharmacokinetics and hemodynamic effects of a combination of verapamil and trandolapril were studied in 20 patients with hypertension (ages 29-71 yr), 10 of whom also had fatty liver disease, who received a sustained-release oral capsule containing 180 mg verapamil and 1 mg trandolapril once daily for 7 days. For verapamil, no statistically significant differences were seen between patients with and without fatty liver with regard to Cmax (110.5 vs 76.5 ug/L), plasma AUC from 0-24 hr (1260.6 vs 941.2 ug/L hr), and elimination half-life (9.8 vs 9.2 hr).
An open, randomized, single dose study of the effects of food on the bioavailability of sustained-release (SR) verapamil hydrochloride (Isoptin) was conducted in 12 healthy volunteers (aged 19-65 yr) who received 240 mg of the SR preparation while fasting or with food and a conventional preparation while fasting. Although the elimination half-life of SR verapamil was unchanged, the time to maximum concentration was prolonged and the area under the concentration-time curve (AUC) was 80% of the regular preparation. Concomitant food administration prolonged the time to maximum concentration from 7.3+-3.4 to 11.7+-6.3 h but had little effect on the maximum concentration, half-life or AUC of SR verapamil.
For more Absorption, Distribution and Excretion (Complete) data for Verapamil (21 total), please visit the HSDB record page.

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Metabolism / Metabolites
Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8.
Metabolites: The main metabolite is norverapamil which has an elimination half-life very similar to that of the parent compound, ranging from 4 to 8 hours. Verapamil undergoes an extensive hepatic metabolism. Due to a large hepatic first-pass effect, bioavailability does not exceed 20 - 35% in normal subjects. Twelve metabolites have been described. The main metabolite is norverapamil and the others are various N- and 0-dealkylated metabolites. Elimination by route of exposure: Kidney: About 70% of the administered dose is excreted in urine within 5 days as metabolites, of which 3-4% is excreted as unchanged drug. Feces: About 16% of the ingested dose is excreted within 5 days in feces as metabolites. Breast milk: Verapamil may appear in breast milk.
Verapamil yields in the dog: 5-(3,4-dimethoxyphenethylamino)-2 -(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile; 2-(3,4-dimethoxyphenyl)-5 -(n-(4-hydroxy-3-methoxyphenethyl)methylamino)-2-isopropylvaleronitrile, and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-methylaminovaleronitrile. The latter was also found in rats. /From table/ /salt not specified/
Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240 mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.
The biotransformation pathway of verapamil, a widely prescribed calcium channel blocker, was investigated by electrochemistry (EC) coupled online to liquid chromatography (LC) and electrospray mass spectrometry (ESI-MS). Mimicry of the oxidative phase I metabolism was achieved in a simple amperometric thin-layer cell equipped with a boron-doped diamond (BDD) working electrode. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass data and additional MS/MS experiments. We were able to demonstrate that all of the most important metabolic products of the calcium antagonist including norverapamil (formed by N-demethylation) can easily be simulated using this purely instrumental technique. Furthermore, newly reported metabolic reaction products like carbinolamines or imine methides become accessible. The results obtained by EC were compared with conventional in vitro studies by conducting incubations with rat as well as human liver microsomes (RLMs, HLMs). Both methods showed good agreement with the data from EC/LC/MS. Thus, it can be noted that EC is very well-suited for the simulation of the oxidative metabolism of verapamil. In summary, this study confirms that EC/LC/MS can be a powerful tool in drug discovery and development when applied complementary to established in vitro or in vivo approaches.
Mechanism-based inactivation (MBI) of cytochrome P450 (CYP) 3A by verapamil and the resulting drug-drug interactions have been studied in vitro, but the inhibition of verapamil on its own metabolic clearance in clinic, namely auto-inhibition of verapamil metabolism, has never been reproduced in vitro. This paper aimed to evaluate the utility of gel entrapped rat hepatocytes in reflecting such metabolic auto-inhibition using hepatocyte monolayer as a control. Despite being a similar concentration- and time-dependent profile, auto-inhibition of verapamil metabolism showed apparent distinctions between the two culture models. Firstly, gel entrapped hepatocytes were more sensitive to such inhibition, which could be largely due to their higher CYP3A activity detected by the formation rates of 6-beta-hydroxy testosterone and 1'-hydroxy midazolam. Furthermore, the inhibitory effect of ketoconazole and verapamil on CYP 3A activity as well as the reduction of verapamil intrinsic clearance (CL(int)) by ketoconazole was only observed in gel-entrapped hepatocytes. In this respect, the involvement of CYP3A in auto-inhibition of verapamil metabolism could be illustrated in gel-entrapped hepatocytes but not in hepatocyte monolayer. All of these results indicated that hepatocytes of gel entrapment reflected more of verapamil metabolic auto-inhibition than hepatocyte monolayer and could serve as a suitable system for investigating drug metabolism.
Verapamil has known human metabolites that include 2-(3,4-dimethoxyphenyl)acetaldehyde, Norverapamil, D-702, M9 (D-703), and D-617.
Route of Elimination: Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug.
Half Life: 2.8-7.4 hours

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Biological Half-Life
Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours.
The pharmacokinetics of verapamil and its metabolite, norverapamil, were studied in 10 patients (ages 19-69 yr) with portal hypertension and in 6 healthy subjects (ages 21-69 yr) who received an oral dose of 80 mg verapamil hydrochloride (Isoptin). The terminal phase half-life of verapamil was 210 hr in controls and 1384 hr in patients.
A toxicokinetic study performed in two cases showed plasma half lives of 7.9 and 13.2 hours, total body clearances of 425 and 298 mL/min. ...

Toxicity Summary
IDENTIFICATION AND USE: Verapamil is the drug of choice for prevention and treatment of paroxysmal supraventricular tachycardia. Verapamil has been shown to be effective in the treatment of angina pectoris. Verapamil may be used as an alternative treatment for mild or moderate hypertension. HUMAN STUDIES: Verapamil has a vasodilating action on the vascular system. Toxic effects occur usually after a delay of 1 to 5 hours following ingestion. After IV injection, symptoms appear after a few minutes. The main cardiovascular symptoms are: bradycardia and atrioventricular block (in 82% of cases) hypotension and cardiogenic shock (in 78% of cases) cardiac arrest (in 18% of cases). Pulmonary edema may occur. Impairment of consciousness and seizures may occur and are related to a low cardiac output. Nausea and vomiting may be observed. Metabolic acidosis due to shock and hyperglycemia may occur. Verapamil is a calcium channel blocker and inhibits the entry of calcium through calcium channels into cardiovascular cells. Verapamil reduces the magnitude of the calcium current entry and decreases the rate of recovery of the channel. Verapamil decreases peripheral vascular and coronary resistance but it is a less potent vasodilator than nifedipine. In contrast, its cardiac effects are more prominent than those of nifedipine. At doses necessary to produce arterial vasodilatation, verapamil has much greater negative chronotropic, dromotropic and inotropic effects than nifedipine. At toxic doses, calcium channel inhibition by verapamil results in three principal effects: hypotension due to arterial vasodilatation, cardiogenic shock secondary to a negative inotropic effect, bradycardia and atrio-ventricular block. The therapeutic effects of verapamil on hypertension and angina pectoris are due to arterial systemic and coronary vasodilatation. The antiarrhythmic activity of verapamil is due to a delay in impulse transmission through the AV node by a direct action. Toxicity may occur after ingestion of 1 g. Verapamil was tested on human peripheral lymphocytes in vitro using micronucleus (MN) test. The MN frequencies showed increase after all treatment. The results of FISH analysis suggest that verapamil, separately or combined with ritodrine, shows to a larger extent aneugenic than clastogenic effect. ANIMAL STUDIES: Verapamil promotes atrial fibrillation in normal dogs. In swine, verapamil toxicity, as defined by a mean arterial pressure of 45% of baseline, was produced following an average verapamil infusion dose of 0.6 +/- 0.12 mg/kg. This dose produced an average plasma verapamil concentration of 728.1 +/- 155.4 ug/L. Hypertonic sodium bicarbonate reversed the hypotension and cardiac output depression of severe verapamil toxicity in a swine model. ECOTOXICITY STUDIES: Effects of long-term exposure of verapamil on mutagenic, hematological parameters and activities of the oxidative enzymes of Nile tilapia, Oreochromis niloticus were investigated for 60 days exposure at the concentrations of 0.29, 0.58 and 1.15 mg/L in the fish liver. The exposure resulted in significantly high micronuclei induction of peripheral blood cells. The indices of oxidative stress biomarkers (lipid peroxidation and carbonyl protein) showed elevated level. There was increase in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST). In other experiments, exposure to sub-lethal concentrations of verapamil (0.14, 0.29 and 0.57 mg/L) for period of 15, 30, 45 and 60 days, led to inhibition of acetylcholinesterase activities in the brain and muscle of the fish. Transcription of catalase (CAT), superoxide dismutase (SOD) and heat shock proteins 70 (hsp70) were up-regulated in both the tissues after the study period. In Carassius auratus, the behavioral alterations were observed in the form of respiratory difficulty and loss of body balance confirming the cardiovascular toxicity caused by verapamil at higher doses. In addition to affecting the cardiovascular system, verapamil also showed effects on the nervous system in the form of altered expression of parvalbumin. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae of common carp (Cyprinus carpio). In the D. magna chronic toxicity test, several parameters, such as the survival percentage, the body length of D. magna, the time of first reproduction, and the number of offspring per female, were adversely affected during the exposure to 4.2 mg/L verapamil. During the 24-hr short-term exposure, verapamil caused a downregulated expression of the CYP4 and CYP314 genes. During the 21-day long-term exposure, verapamil significantly reduced the expression level of the Vtg gene, a biomarker of the reproduction ability in an oviparous animal.
Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on L-type calcium channels in the heart causes a reduction in ionotropy and chronotropy, thuis reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is thought to be linked to its calcium-channel blocker effect, but which channel subtypes are involved is presently not known.

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Toxicity Data
LD50: 8 mg/kg (Intravenous, Mouse) (A308)

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Interactions
Drug interactions: protein-bound drugs
Drug Interactions: beta-adrenergic blocking agents
Drug Interactions: digoxin
Drug Interactions: hypotensive agents
For more Interactions (Complete) data for Verapamil (42 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip 68 mg/kg /Verapamil hydrochloride/
LD50 Rat ip 67 mg/kg /Verapamil hydrochloride/
LD50 Rat oral 114 mg/kg /Verapamil hydrochloride/
LD50 Mouse iv 7.6 mg/kg /Verapamil hydrochloride/
For more Non-Human Toxicity Values (Complete) data for Verapamil (14 total), please visit the HSDB record page.

[1]. Verapamil as a culprit of palbociclib toxicity. J Oncol Pharm Pract. 2019 Apr;25(3):743-746.

[2]. Krikler DM. Verapamil in arrhythmia. Br J Clin Pharmacol. 1986;21 Suppl 2:183S-189S.

[3]. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J. 1996 Jan;17(1):76-81.

[4]. Blood-to-Retina Transport of Fluorescence-Labeled Verapamil at the Blood-Retinal Barrier. Pharm Res. 2018 Mar 12;35(5):93.

[5]. Anti-arrhythmic effect of Verapamil is accompanied by preservation of cx43 protein in rat heart. PLoS One. 2013 Aug 12;8(8):e71567.

Therapeutic Uses
Anti-Arrhythmia Agents; Calcium Channel Blockers; Vasodilator Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Verapamil hydrochloride is included in the database.
Oral calcium-channel blocking agents are considered the drugs of choice for the management of Prinzmetal variant angina. A nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) also has been recommended in patients with unstable angina who have continuing or ongoing ischemia when therapy with beta-blocking agents and nitrates is inadequate, not tolerated, or contraindicated and when severe left ventricular dysfunction, pulmonary edema, or other contraindications are not present. In the management of unstable or chronic stable angina pectoris, verapamil appears to be as effective as beta-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates. In unstable or chronic stable angina pectoris, verapamil may reduce the frequency of attacks, allow a decrease in sublingual nitroglycerin dosage, and increase the patient's exercise tolerance. /Included in US product label/
Verapamil is used for rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including tachycardia associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome; the drug also is used for control of rapid ventricular rate in nonpreexcited atrial flutter or fibrillation. The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of verapamil in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia (AVNRT)); in general, IV verapamil is recommended for acute treatment, while oral verapamil is recommended for ongoing management of these arrhythmias. /Included in the US product label/
For more Therapeutic Uses (Complete) data for Verapamil (14 total), please visit the HSDB record page.

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Drug Warnings
...Concurrent treatment /of verapamil & beta-blockers/ in those with impaired left ventricular function could be dangerous if...a 10-15% depression in myocardial function takes place. /Salt not specified/
...Absolute contraindications to the use of verapamil (the acute stage of myocardial infarction, complete atrioventricular block, cardiogenic shock, overt heart failure)...should not be injected together with a beta-adrenergic blocking agent, or within 3 times the half-life of that agent. /Salt not specified/
The basic physiologic actions of verapamil may lead to serious adverse effects. /Salt not specified/
Maternal Medication usually Compatible with Breast-Feeding: Verapamil: Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/ /Salt not specified/
For more Drug Warnings (Complete) data for Verapamil (23 total), please visit the HSDB record page.

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Pharmacodynamics
Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions.

C27H38N2O4

454.61

454.283

C, 71.34; H, 8.43; N, 6.16; O, 14.08

52-53-9

Verapamil hydrochloride;152-11-4; 38321-02-7 (dexverapamil)

2520

Viscous, pale yellow oil

1.1±0.1 g/cm3

586.2±50.0 °C at 760 mmHg

25°C

308.3±30.1 °C

0.0±1.6 mmHg at 25°C

1.526

3.9

63.95

0

6

13

33

606

0

CC(C)C(CCCN(C)CCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC

SGTNSNPWRIOYBX-UHFFFAOYSA-N

InChI=1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3

2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile

NSC-135784; NSC 135784; VERAPAMIL; 52-53-9; Iproveratril; Dilacoran; Vasolan; Isoptimo; Isoptin; Verapamilo; Verapamil

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~219.97 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.50 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.50 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.50 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。