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Drotaverine Hydrochloride is a novel and potent inhibitor of phosphodiesterase 4 with antispasmodic activity. It has been used to enhance cervical dilation during childbirth. It is structurally related to papaverine and has no anticholinergic effects. Drotaverine is also an L-type voltage-dependent calcium channel (L-VDCC) blocker, blocking the degradation of 3',5'-cyclic adenosine monophosphate.
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Drotaverine is not completely absorbed following oral administration and its bioavailability is highly variable. Following oral administration of a single 80 mg dose, the absolute bioavailability ranged between 24.5 and 91 % with a mean of 58.2 ± 18.2%. Mean Cmax was 292 ± 88 ng/mL. Mean AUC was 3251 ± 950 ng*h/mL. Mean Tmax was 1.9 ± 0.54 hours. Drotaverine is mainly eliminated via hepatic metabolism. About 67% of the drug is found in feces and 20% of the drug was eliminated with urine. Following oral administration of a single 80 mg dose, the mean volume of distribution was 193 ± 48 L. Following an intravenous dose of 80 mg, the mean volume of distribution was 195 ± 48 L. Following oral administration of a single 80 mg dose, the mean renal clearance was 0.59 ± 0.18 mL/min. Following an intravenous dose of 80 mg, the mean renal clearance was 0.73 ± 0.29 mL/min. Metabolism / Metabolites Drotaverine is reported to undergo extensive hepatic metabolism, which is its main route of elimination. It may also undergo biliary excretion to form conjugated metabolites. Proposed metabolic pathways and metabolites are based on limited animal studies: in rats, the major identified metabolites of drotaverine are 4'-desethyl-drotaverine, 6-desethyl-drotaverine, drotaveraldine, and 4'-desethyl-drotaveraldine, all of which are glucuronidated in the bile. 4'-desethyl-drotaveraldine was the most predominant metabolite eliminated into the bile. Biological Half-Life Following oral administration of a single 80 mg dose, the mean half-life was 9.11 ± 1.29 hours. Following an intravenous dose of 80 mg, the mean half-life 9.33 ± 1.02 hours. |
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| Toxicity/Toxicokinetics |
Protein Binding
There is no information available. |
| References | |
| Additional Infomation |
Drotaverine is a member of isoquinolines.
Drotaverine is an antispasmodic drug that works by inhibiting phosphodiesterase-4 (PDE4). It is a benzylisoquinoline derivative that is structurally related to [papaverine], although it displays more potent antispasmodic activities than papaverine. Drotaverine has been used in the symptomatic treatment of various spastic conditions, such as gastrointestinal diseases, biliary dyskinesia, and vasomotor diseases associated with smooth muscle spasms. It also has been investigated in dysmenorrhea, abortion, and augmentation of labour. More recently, drotaverine gained attention in the treatment of benign prostatic hyperplasia, parainfluenza, and avian influenza viruses. Drotaverine is not approved by the FDA, European Medicines Agency, or Health Canada. It is approved for use in Thailand as oral tablets or intramuscular injections. Drug Indication Drotaverine is used to alleviate gastrointestinal and genitourinary smooth muscle spasms, such as cholecystitis and gallbladder disorders. Mechanism of Action Drotaverine is a selective inhibitor of phosphodiesterase 4 (PDE4), which is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to elevated levels of cAMP, leading to smooth muscle relaxation. Recent research showed that low levels of cAMP have been associated with brain tumorigenesis, leading to the investigation of PDE4 inhibitors as potential anticancer agents. Pharmacodynamics Drotaverine is an e spasmolytic agent with a relaxing effect on smooth muscles. It works to relieve visceral spasms and improve cervical dilation. _In vitro_, drotaverine mediated cytostatic effects on several human tumor cell lines and nonmalignant mouse fibroblasts. Drotaverine may have minor allosteric calcium channel blocking properties: _in vitro_, drotaverine behaves like voltage-dependent L-type calcium channel blockers. |
| Molecular Formula |
C24H31NO4.HCL
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|---|---|
| Molecular Weight |
433.96818
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| Exact Mass |
433.201
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| CAS # |
985-12-6
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| Related CAS # |
Drotaverine-d10 hydrochloride
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| PubChem CID |
1712095
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| Appearance |
White to light yellow solid powder
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| Density |
1.097 g/cm3
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| Boiling Point |
564ºC at 760 mmHg
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| Melting Point |
208-212ºC
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| Flash Point |
240.7ºC
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| LogP |
6.056
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
29
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| Complexity |
511
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOC1=CC=C(/C=C\2/C3=C(CCN2)C=C(C(=C3)OCC)OCC)C=C1OCC.Cl
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| InChi Key |
OMFNSKIUKYOYRG-MOSHPQCFSA-N
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| InChi Code |
InChI=1S/C24H31NO4/c1-5-26-21-10-9-17(14-22(21)27-6-2)13-20-19-16-24(29-8-4)23(28-7-3)15-18(19)11-12-25-20/h9-10,13-16,25H,5-8,11-12H2,1-4H3/b20-13-
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| Chemical Name |
(1Z)-1-[(3,4-diethoxyphenyl)methylidene]-6,7-diethoxy-3,4-dihydro-2H-isoquinoline
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
H2O : ~100 mg/mL (~230.43 mM)
DMSO : ~62.5 mg/mL (~144.02 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.79 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 (4.79 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.79 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3043 mL | 11.5215 mL | 23.0431 mL | |
| 5 mM | 0.4609 mL | 2.3043 mL | 4.6086 mL | |
| 10 mM | 0.2304 mL | 1.1522 mL | 2.3043 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00731198 | COMPLETEDWITH RESULTS | Drug: Drotaverine hydrochloride Drug: Hyoscine-N-butylbromide |
Bile Duct Diseases ERCP Pancreatic Diseases |
Changhai Hospital | 2008-08 | Phase 3 |
| NCT01639027 | COMPLETED | Drug: Drotaverine Drug: Placebo |
Failure of Cervical Dilation as Antepartum Condition Labor Pain Mild Birth Asphyxia, APGAR 4-7 Prolonged First Stage of Labor |
Ain Shams Maternity Hospital | 2012-05 | Phase 2 Phase 3 |
| NCT02026427 | COMPLETED | Orthopedic Patients Spinal Anesthesia Urinary Retention |
Military Institute od Medicine National Research Institute |
2010-08 | ||
| NCT03744130 | UNKNOWN STATUS | Diagnostic Test: Contrast-enhanced Ultrasound | Inflammatory Bowel Disease | State Scientific Centre of Coloproctology, Russian Federation |
2018-01-10 | Not Applicable |
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