Diltiazem (200 µM) causes a use-dependent blockage in a modest number of pulses [1]. Diltiazem lowers Ca2+ inflow by speeding up inactivation during action potentials, and the use-dependent blockage is caused by an increase in the number of channels that remain closed for an extended period of time.

Aortic aneurysm formation is prevented by diltiazem (100 mg/kg; po; for 4 weeks) in a way that is independent of blood pressure[3]. Diltiazem inhibits the growth of aortic aneurysms in mice via having an anti-inflammatory action on monocytic cells that is independent of blood pressure[3]. Rats given Diltiazem (2 mg/kg; IV) show T1/2 of 61.2 min and CLel of 3.2 mL/min[4].

Animal/Disease Models: Male ApoE−/− mice, angiotensin II induced aneurysms[3]
Doses: 100 mg/kg
Route of Administration: Oral administration, in drinking water, for 4 weeks
Experimental Results: Srongly decreased the vascular remodeling but also lowered the blood pressure.

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Animal/Disease Models: Rat (200-250 g)[4]
Doses: 2 mg/kg ( pharmacokinetic/PK Analysis)
Route of Administration: intravenous (iv) injection
Experimental Results: T1/2 (61.2 min), CLel (3.2 mL/min)

Absorption, Distribution and Excretion
Diltiazem is readily absorbed from the gastrointestinal tract. The lowest therapeutic plasma concentration of diltiazem ranges from 50 to 200 ng/mL. Following oral administration of a 360 mg extended-release formulation, the drug is detectable in plasma within 3 to 4 hours, with peak plasma concentrations reached 11 to 18 hours post-administration. Food intake does not affect peak concentrations or systemic exposure of diltiazem. Due to first-pass metabolism in the liver, the absolute bioavailability after oral administration is approximately 40%, but due to significant individual variability in the first-pass effect, it ranges from 24% to 74%. Bioavailability may be increased in patients with hepatic impairment. Due to its extensive metabolism, only 2% to 4% of the unchanged drug is detectable in urine. The main metabolite in the urine of healthy volunteers was N-monodesyldiltiazem, followed by deacetylated N,O-didesyldiltiazem, deacetylated N-monodesyldiltiazem, and deacetylateddiltiazem; however, there appeared to be significant inter-individual variability in the urinary excretion of DTZ and its metabolites. Following a single intravenous injection of diltiazem in healthy male volunteers, the apparent volume of distribution was approximately 305 L. Following a single intravenous injection of diltiazem in healthy male volunteers, the systemic clearance was approximately 65 L/h. After constant-rate intravenous infusion, the systemic clearance decreased to 48 L/h. Diltiazem has a protein binding rate of 80-90% and a volume of distribution of approximately 5.3 L/kg. After oral administration of diltiazem, its clearance follows first-order kinetics, with a half-life of 5-10 hours, independent of intake. However, in sustained-release formulations, the time to peak absorption is delayed due to sustained gastrointestinal absorption, and the half-life may also be significantly prolonged. Although diltiazem and other drugs are almost completely absorbed after oral administration, their bioavailability is reduced, and in some cases significantly reduced, due to first-pass hepatic metabolism. The effects of these drugs are apparent within 30-60 minutes after oral administration. With repeated oral administration, bioavailability and half-life may increase due to hepatic metabolic saturation. The main metabolite of diltiazem is desacetylated diltiazem, which has approximately half the vasodilatory potency of diltiazem. Diltiazem is secreted into human milk. This study investigated the pharmacokinetic changes of diltiazem and its main metabolite, desacetylated diltiazem (DAD), after oral administration to normal rabbits and rabbits with mild to moderate folic acid-induced renal failure. In the experiment, rabbits were orally administered diltiazem at 10 mg/kg (n=6). The concentrations of diltiazem and DAD in plasma were determined using high-performance liquid chromatography (HPLC). The results showed that the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) were significantly increased in rabbits with mild and moderate folate-induced renal failure. The metabolite ratio of diltiazem to DAD was significantly decreased in both models. The volume of distribution (Vd) and total clearance (CLt) of diltiazem were also significantly decreased. The elimination rate constant (β) of diltiazem was significantly decreased in the folate-induced renal failure rabbit model, while the elimination rate constant of DAD was significantly increased. These results indicate that hepatic metabolism of diltiazem is inhibited…
The pharmacokinetics of diltiazem after subconjunctival and topical administration in rabbits were investigated. Dltiazem successfully penetrated into the aqueous humor of rabbit eyes. The peak aqueous humor concentration was 3.8 ± 0.4 μg/ml after topical administration and 15.3 ± 1.1 μg/ml after subconjunctival injection. In both cases, peak plasma drug concentrations were reached at 1.5 hours post-administration.

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Metabolism/Metabolites
Diltiazem undergoes extensive first-pass metabolism, explaining its relatively low oral bioavailability. It is primarily N-demethylated via CYP3A4. CYP2D6 is responsible for O-demethylation, with esterase-mediated deacetylation. There is significant individual variability in the circulating levels of metabolites in the plasma of healthy volunteers. In healthy volunteers, the major circulating metabolites in plasma are N-monodemethyldiltiazem, deacetylateddiltiazem, and deacetylatedN-monodemethyldiltiazem, all of which are pharmacologically active. Deacetylateddiltiazem retains approximately 25-50% of the pharmacological activity of the parent compound. Deacetylateddiltiazem can be further converted to deacetylateddiltiazem N-oxide or deacetylatedO-demethyldiltiazem. N-monodemethyldiltiazem can be further metabolized to N,O-didemethyldiltiazem. Deacetylated N-monodemethyldaltiazem can be further metabolized to deacetylated N,O-diodemethyldaltiazem, which can undergo glucuronidation or sulfation. Daltiazem can be O-demethylated by CYP2D6 to generate O-demethyldaltiazem. The major metabolite of diltiazem is deacetylated diltiazem, which has approximately half the vasodilatory potency of diltiazem. Daltiazem is extensively metabolized in the liver and extrahepatic tissues. Deacetylated diltiazem (M1) and N-demethyldaltiazem (MA) are the two main basic metabolites of diltiazem, which retain pharmacological activity. Prolonged use of this drug in adult patients can impair its metabolism. Known metabolites of diltiazem include O-demethyldaltiazem and N-demethyldaltiazem. Daltiazem is metabolized by the CYP3A4 enzyme and acts as its inhibitor.
Half-life: 3.0 - 4.5 hours

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Biological Half-life
After a single or multiple oral administration, the plasma elimination half-life is approximately 3.0 to 4.5 hours. The half-life may be slightly prolonged with dose and degree of hepatic impairment. After a single or multiple doses of extended-release tablets, the apparent elimination half-life of diltiazem is 6 to 9 hours. After a single intravenous injection, the plasma elimination half-life is approximately 3.4 hours. The elimination half-life of the pharmacologically active metabolite is longer than that of diltiazem. The elimination of oral diltiazem follows first-order kinetics, with a half-life of 5-10 hours…

Toxicity Summary
Diltiazem, similar to verapamil, may inhibit the influx of extracellular calcium ions across the membranes of cardiomyocytes and vascular smooth muscle cells by altering ion channel structure, inhibiting ion gating mechanisms, and/or interfering with the release of calcium ions from the sarcoplasmic reticulum. This leads to inhibition of myocardial smooth muscle cell contraction, resulting in coronary and systemic arterial dilation and improved oxygen delivery to myocardial tissue. Hepatotoxicity
Diltiazem treatment is associated with a low incidence of mild, transient elevations in serum transaminase levels, which are usually asymptomatic and often resolve with continued treatment. Clinically significant acute liver injury with jaundice caused by diltiazem is rare, with only sporadic case reports. Calcium channel blockers are rarely mentioned in extensive case series of drug-induced liver injury. Most cases attributed to diltiazem have a short latency period (3 to 14 days) and are characterized by hypersensitivity reactions such as fever, rash, and eosinophilia. The types of liver injury range from cholestatic to hepatocellular. Jaundice is usually absent, or if it does occur, it is usually mild. No autoantibody formation has been reported. Therefore, liver injury caused by diltiazem is likely specific, usually mild, and self-limiting, recovering within 4 to 8 weeks after discontinuation. Acute liver injury is listed as a possible adverse event on the diltiazem product label.
Probability Score: C (Possible but rare, a clinically significant cause of liver injury).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Based on limited data, the amount of diltiazem ingested by infants is small and is not expected to have any adverse effects on breastfed infants.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
Protein Binding
Based on in vitro binding studies, diltiazem binds to approximately 70-80% of plasma proteins. Approximately 40% of the drug is believed to bind to α-1-glycoprotein at clinically significant concentrations, while approximately 30% binds to albumin. Toxicity Data: LD50 = 740 mg/kg (oral in mice) Interactions: Diltiazem interacts with propranolol by inhibiting first-pass metabolism, reducing oral clearance and leading to increased propranolol concentrations. A dose reduction of propranolol may be necessary. (Data from table) Diltiazem interacts with cyclosporine, increasing cyclosporine concentrations. After initiating diltiazem administration, the cyclosporine dose should be reduced, and cyclosporine concentrations should be monitored. (Data from table) Diltiazem interacts with disopyramide and flecainide, causing heart failure through additive inhibition of myocardial contractility. (Data from table) Use should be avoided whenever possible, especially in patients with impaired myocardial function. /Excerpt from table/
Diltiazem interacts with amiodarone and flecainide, causing sinus arrest and cardiac conduction block by cumulatively inhibiting sinoatrial node function and atrioventricular node conduction. Extreme caution must be exercised when using these medications in combination. /Excerpt from table/
For more complete data on diltiazem (a total of 15 drug interactions), please visit the HSDB record page.

[1]. Diltiazem facilitates inactivation of single L-type calcium channels in guinea pig ventricular myocytes. Jpn Heart J. 2003 Nov;44(6):1005-14.

[2]. S Lin Tang, et l. Structural Basis for Diltiazem Block of a Voltage-Gated Ca2+ Channel. Mol Pharmacol. 2019 Oct; 96(4): 485-492.

[3]. L-type calcium channel inhibitor diltiazem prevents aneurysm formation by blood pressure-independent anti-inflammatory effects. Hypertension. 2013 Dec;62(6):1098-104.

[4]. Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects. Br J Pharmacol. 1987 Aug; 91(4): 735-745.

Therapeutic Uses
Diltiazem… can reduce the probability of recurrent myocardial infarction in patients who have experienced their first non-Q wave myocardial infarction and are not suitable for use with β-adrenergic receptor antagonists. … Diltiazem… has been shown to relieve symptoms of Raynaud's disease. … Diltiazem… can be used alone or in combination with other drugs for the treatment of hypertension. (Included in the US product label) … Diltiazem for injection is indicated for the treatment of supraventricular tachycardia. Diltiazem… can rapidly convert paroxysmal supraventricular tachycardia (including tachycardia associated with accessory conduction pathways, such as Wolff-Parkinson-White [WPW] syndrome or Lown-Ganong-Levine [LGL] syndrome) to sinus rhythm, especially in patients unresponsive to vagal stimulation {161}, and atrioventricular nodal reentry is necessary to maintain tachycardia {125}. Diltiazem for injection...can also temporarily control rapid ventricular rates in patients with atrial flutter or atrial fibrillation. .../US product label contains/
For more complete data on the therapeutic uses of diltiazem (16 types), please visit the HSDB record page.

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Drug Warnings
Toxicity of sustained-release calcium channel blockers may occur more than 12 hours after administration. All patients with overdose of sustained-release calcium channel blockers should be hospitalized for observation, even if asymptomatic. /Calcium Channel Blockers/
Discontinuation of calcium channel blockers in patients with severe hypertension may induce myocardial infarction, even in patients without a history of angina or myocardial infarction. There have been reports of worsening angina and myocardial infarction following discontinuation of calcium channel blockers in patients receiving treatment for ischemic chest pain and with normal coronary angiography. Calcium Channel Blockers
Diltiazem, especially intravenously, should not be used in patients with ventricular dysfunction, sinoatrial node or atrioventricular node conduction disorders, or systolic blood pressure below 90 mmHg. The most common adverse cardiovascular reaction to intravenous diltiazem is symptomatic or asymptomatic hypotension, occurring in 3.2% and 4.3% of patients, respectively, in clinical trials. In patients receiving oral diltiazem, approximately 1% or less experience hypotension or orthostatic hypotension. If symptomatic hypotension occurs, appropriate treatment measures should be taken immediately (e.g., head-down position, fluid resuscitation). Hypotension occurs due to the vasodilatory effect of diltiazem on vascular smooth muscle. In clinical trials, 1.7% of patients receiving intravenous diltiazem experienced vasodilation or flushing; this proportion was approximately 1% or less in patients receiving oral diltiazem. For more complete data on drug warnings for diltiazem (18 in total), please visit the HSDB record page.

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Pharmacodynamics
Diltiazem is an antihypertensive and vasodilator that works by lowering blood pressure through relaxation of vascular smooth muscle. This is related to long-term treatment efficacy, as lowering blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, primarily stroke and myocardial infarction. Diltiazem inhibits the influx of extracellular calcium ions into the cell membranes of myocardial and vascular smooth muscle during depolarization. Diltiazem is classified as a negative inotropic agent (reducing myocardial contractility) and a negative chronotropic agent (reducing heart rate). Diltiazem is also considered a heart rate controller because it lowers heart rate. Diltiazem exerts its hemodynamic effects by lowering blood pressure, systemic vascular resistance, the heart rate-blood pressure product, and coronary vascular resistance, while simultaneously increasing coronary blood flow. Diltiazem can reduce sinoatrial node and atrioventricular conduction in isolated tissues and exhibits a negative inotropic effect in isolated specimens. In supraventricular tachycardia, diltiazem can prolong the atrioventricular node refractory period. Because the magnitude of blood pressure reduction is correlated with the degree of hypertension, the antihypertensive effect of diltiazem is most significant in hypertensive patients. In a randomized, double-blind, parallel-group, dose-response study of patients with essential hypertension, patients taking 120, 240, 360, and 540 mg of diltiazem experienced reductions in diastolic blood pressure of 1.9, 5.4, 6.1, and 8.6 mmHg, respectively. The placebo group showed a reduction of only 2.6 mmHg. In another randomized, double-blind study of patients with chronic stable angina, different bedtime doses of diltiazem improved exercise tolerance 21 hours after administration compared to the placebo group. The NORDIL study in hypertensive patients evaluated the therapeutic effects of diltiazem in reducing cardiovascular disease morbidity and mortality. When considering the composite primary endpoint of fatal and nonfatal stroke, myocardial infarction, and other cardiovascular deaths, the diltiazem group showed a 25% reduction in the incidence of fatal and nonfatal stroke. Although the clinical significance of this effect is unclear, it suggests that diltiazem may have a protective effect against stroke in hypertensive patients.

C22H26N2O4S

414.52

414.161

42399-41-7

Diltiazem hydrochloride;33286-22-5;Diltiazem malate;144604-00-2;Diltiazem-d6;1242184-41-3

39186

White to off-white solid powder

1.3±0.1 g/cm3

594.4±50.0 °C at 760 mmHg

104-106°C (lit.)

313.3±30.1 °C

0.0±1.7 mmHg at 25°C

1.621

3.63

0

6

7

29

565

2

CC(=O)O[C@@H]1[C@@H](SC2=CC=CC=C2N(C1=O)CCN(C)C)C3=CC=C(C=C3)OC

HSUGRBWQSSZJOP-RTWAWAEBSA-N

InChI=1S/C22H26N2O4S/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3/h5-12,20-21H,13-14H2,1-4H3/t20-,21+/m1/s1

(2S,3S)-5-(2-(dimethylamino)ethyl)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate

CRD 401 DiltiazemCRD-401 DilticardCRD401 Dilzen

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)

DMSO : ~100 mg/mL (~241.24 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)