Ranolazine (formerly CVT-303, RS 43285-003; brand name Ranexa) is a approved anti-angina drug used to treat chronic angina. Ranolazine acts as a calcium uptake inhibitor via the sodium/calcium channel. As an anti-ischemic agent, it inhibits late sodium current that results in a reduction of Na+ dependent Ca2+ overload.

Physicochemical Properties

Molecular Formula	C24H33N3O4
Molecular Weight	427.54
Exact Mass	427.247
CAS #	95635-55-5
Related CAS #	Ranolazine dihydrochloride;95635-56-6;Ranolazine-d3;1054624-77-9;Ranolazine-d5;1092804-87-9;Ranolazine-d8;1092804-88-0
PubChem CID	56959
Appearance	White to off-white solid powder
Density	1.2±0.1 g/cm3
Boiling Point	624.1±55.0 °C at 760 mmHg
Melting Point	119-1200C
Flash Point	331.2±31.5 °C
Vapour Pressure	0.0±1.9 mmHg at 25°C
Index of Refraction	1.586
LogP	3.47
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	9
Heavy Atom Count	31
Complexity	531
Defined Atom Stereocenter Count	0
InChi Key	XKLMZUWKNUAPSZ-UHFFFAOYSA-N
InChi Code	InChI=1S/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29)
Chemical Name	N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide
Synonyms	Ranolazine Dihydrochloride;CVT 303, RS 43285-003;Ranolazine;S 43285; RS-43285; RS43285; CVT-303; CVT303; Ranexa; Latixa; Ranolazine HCl; Ranolazine Hydrochloride.
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
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

ln Vitro	In vitro activity: Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure in myocardial cells. Ranolazine significantly and reversibly shortens the action potential duration (APD) of myocytes stimulated at either 0.5 Hz or 0.25 Hz in a concentration-dependent manner in left ventricular myocytes of dogs. Ranolazine at 5 and 10 mM reversibly shortens the duration of twitch contractions (TC) and abolished the after contraction. Ranolazine is found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL).
ln Vivo	In rats undergoing left anterior descending coronary artery occlusion-reperfusion, ranolazine (bolus injection 10 mg/kg and infusion 9.6 mg/kg/h; bolus injection; for 145 minutes; male Wistar rats) therapy dramatically lowers infarct size and cardiac troponin T release [3].
Animal Protocol	Animal/Disease Models: Male Wistar rats (240-350 g)[3] Doses: Bolus injection 10 mg/kg and infusion (9.6 mg/kg/h) Route of Administration: Bolus injection; for 145 minutes Experimental Results: Dramatically decreased infarct size and cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.
ADME/Pharmacokinetics	Absorption, Distribution and Excretion The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%. From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug. The mean apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L. The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%. Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. ... Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-t increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food. After oral administration of ranolazine, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of (14)C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from ranolazine tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine. Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 ug/mL, ranolazine is approximately 62% bound to human plasma proteins. It is not known whether ranolazine is distributed into milk. For more Absorption, Distribution and Excretion (Complete) data for Ranolazine (7 total), please visit the HSDB record page. Metabolism / Metabolites Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated. Ranolazine is extensively metabolized in the intestine and liver by the cytochrome P-450 (CYP) isoenzyme system, mainly by CYP3A and, to a lesser extent, CYP2D6. In vitro studies indicate that ranolazine also is a p-glycoprotein substrate. At least 4 metabolites of ranolazine have been identified. The pharmacologic activity of these metabolites has not been fully established. Ranolazine is metabolized rapidly and extensively in the liver and intestine ... The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine... Biological Half-Life The apparent terminal half-life of ranolazine is 7 hours. ... Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). ... ... The four most abundant metabolites in plasma ... display apparent half-lives ranging from 6 to 22 hours.
Toxicity/Toxicokinetics	Hepatotoxicity In large preregistration clinical trials, ranolazine was not associated with serum aminotransferase and alkaline phosphatase elevations during treatment and no instances of symptomatic acute liver injury were reported. Since its approval and more wide spread use, ranolazine has been linked to a single instance of mildly symptomatic, rapidly reversible, anicteric liver injury (Case 1). Immunoallergic and autoimmune features were not present. Recovery was rapid once ranolazine was discontinued. Likelihood score: D (possible rare cause of clinically apparent liver injury). Protein Binding Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein. Interactions Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold Ranolazine is a substrate and an inhibitor of the p-glycoprotein transport system; potential pharmacokinetic interactions with p-glycoprotein inhibitors (increased absorption of ranolazine). When ranolazine is co-administered with other substrates, dosage of such drugs may have to be reduced. Potential pharmacodynamic interaction (possible additive effects on QT interval). Ranolazine should be avoided in patients receiving drugs that are known to prolong the QT interval (eg, class Ia (eg, quinidine) or III (eg, dofetilide, sotalol) antiarrhythmic agents, antipsychotic agents (eg, thioridazine, ziprasidone)). Potential pharmacokinetic interaction (increased plasma ranolazine concentrations). Ranolazine should not be used with ketoconazole (a potent CYP3A inhibitor) or itraconazole. For more Interactions (Complete) data for Ranolazine (17 total), please visit the HSDB record page.
References	[1]. Keating GM. Ranolazine: a review of its use as add-on therapy in patients with chronic stable angina pectoris. Drugs. 2013 Jan;73(1):55-73. [2]. Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther. 2008 Jun;325(3):875-81. [3]. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol. 2001 Apr 20;418(1-2):105-10.
Additional Infomation	Therapeutic Uses Enzyme Inhibitors; Angina Pectoris/drug therapy Ranolazine is indicated for the treatment of chronic angina. Ranolazine may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. /Included in US product label/ Drug Warnings Ranolazine is contraindicated in patients: taking strong inhibitors of CYP3A; taking inducers of CYP3A; with clinically significant hepatic impairment. Ranolazine has been shown to prolong the QT interval corrected for rate (QTc) in a dose-related manner. Although the clinical importance of QTc interval prolongation associated with ranolazine is not known, other drugs with this potential have been associated with torsades de pointes-type arrhythmias and sudden death. The mean effect on QTc interval with repeated dosing of ranolazine 1 g twice daily, at time of maximum plasma concentration (Tmax), is about 6 msec; however, in 5% of the population the prolongation of QTc interval is 15 msec. Age, weight, gender, race, heart rate, NYHA class I to IV CHF, and diabetes have no substantial effect on the relationship between ranolazine plasma concentrations and increases in QTc interval. The relationship between ranolazine concentrations and QTc remains linear over a concentration range up to fourfold greater than the concentrations produced by a ranolazine dosage of 1 g twice daily, and is not affected by changes in heart rate. The manufacturer states that ranolazine dosages exceeding 1 g twice daily should not be used. The effects of ranolazine in patients with preexisting QT interval prolongation or receiving concomitant therapy with drugs that are known to prolong the QT interval have not been established. Because of possible additive effects on the QT interval, the manufacturer states that use of ranolazine should be avoided in patients with known QT interval prolongation (including congenital long QT syndrome and uncorrected hypokalemia), known history of ventricular tachycardia, and in patients receiving drugs that prolong the QTc interval (eg, class Ia (eg, quinidine) or III (eg, dofetilide, sotalol) antiarrhythmic agents, antipsychotic agents eg, thioridazine, ziprasidone). Because the QTc-prolonging effect is increased approximately threefold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with mild, moderate, or severe hepatic impairment. For more Drug Warnings (Complete) data for Ranolazine (16 total), please visit the HSDB record page. Pharmacodynamics Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise.

Solubility Data

Solubility (In Vitro)

DMSO: 86 mg/mL (201.2 mM) Water:<1 mg/mL Ethanol: 20 mg/mL (46.8 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.87 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.87 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.87 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3390 mL	11.6948 mL	23.3896 mL
	5 mM	0.4678 mL	2.3390 mL	4.6779 mL
	10 mM	0.2339 mL	1.1695 mL	2.3390 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.