Identification
- Name
- Midazolam
- Accession Number
- DB00683 (APRD00680)
- Type
- Small Molecule
- Groups
- Approved, Illicit
- Description
Midazolam is a short-acting hypnotic-sedative drug with anxiolytic, muscle relaxant, anticonvulsant, sedative, hypnotic, and amnesic properties [6]. It belongs to a class of drugs called benzodiazepines. This drug is unique from others in this class due to its rapid onset of effects and short duration of action [6]. Midazolam is available by oral, rectal, intranasal, intramuscular (IM), and intravenous (IV) routes and has been used in dentistry, cardiac surgery, endoscopic procedures, as pre-anesthetic medication, and as an adjunct to local anesthesia [12].
In late 2018, the intramuscular preparation was approved by the FDA for the treatment of status epilepticus in adults [Label]. Midazolam is considered a schedule IV drug in the United States. This category is defined by drugs, substances, or chemicals with a low potential for abuse and low risk of dependence [9]. This drug was initially approved by the US FDA in 1985, and has been approved for various indications since [Label].
- Structure
Structure for Midazolam (DB00683)
- Synonyms
- Midazolam
- Midazolamum
- External IDs
- Dea No. 2884 / Ro 21-3981/001 / Ro 21-3981/003
- Product Ingredients
Ingredient UNII CAS InChI Key Midazolam hydrochloride W7TTW573JJ 59467-96-8 PLYSCVSCYOQVRP-UHFFFAOYSA-N Midazolam maleate 77520S18SE 59467-94-6 XYGVIBXOJOOCFR-BTJKTKAUSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Buccolam Solution 7.5 mg Buccal Shire Services Bvba 2011-09-05 Not applicable EU 
Buccolam Solution 5 mg Buccal Shire Services Bvba 2011-09-05 Not applicable EU Buccolam Solution 2.5 mg Buccal Shire Services Bvba 2011-09-05 Not applicable EU Buccolam Solution 10 mg Buccal Shire Services Bvba 2011-09-05 Not applicable EU Midazolam Injection Solution 1 mg Intramuscular; Intravenous Fresenius Kabi 2001-03-26 Not applicable Canada 
Midazolam Injection Solution 1 mg Intramuscular; Intravenous Sandoz Canada Incorporated 1999-07-21 Not applicable Canada Midazolam Injection Solution 1 mg Intramuscular; Intravenous Novopharm Limited 2001-12-17 Not applicable Canada Midazolam Injection Liquid 5 mg Intramuscular; Intravenous Fresenius Kabi 2001-03-26 Not applicable Canada Midazolam Injection Solution 5 mg Intramuscular; Intravenous Mylan Pharmaceuticals Not applicable Not applicable Canada Midazolam Injection Solution 5 mg Intramuscular; Intravenous Pfizer 2015-03-31 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Apo-midazolam Injectable 1 mg/ml Liquid 1 mg Intramuscular; Intravenous Apotex Corporation 2001-04-10 2013-08-02 Canada Apo-midazolam Injectable 5 mg/ml Liquid 5 mg Intramuscular; Intravenous Apotex Corporation 2001-04-10 2013-08-02 Canada Midazolam Injection 5 mg/1mL Intramuscular; Intravenous West-Ward Pharmaceuticals Corp. 2000-06-20 Not applicable US 
Midazolam Injection 5 mg/1mL Intramuscular; Intravenous Cardinal Health 2000-06-20 2016-09-30 US Midazolam Injection 1 mg/1mL Intramuscular; Intravenous Cardinal Health 2000-06-20 2015-08-31 US Midazolam Injection, solution 1 mg/1mL Intramuscular; Intravenous The Medicines Company 2000-07-14 Not applicable US Midazolam Injection, solution 5 mg/1mL Intramuscular; Intravenous Athenex Pharmaceutical Division, Llc. 2016-12-14 Not applicable US Midazolam Injection, solution 5 mg/1mL Intramuscular; Intravenous Sagent Pharmaceuticals 2012-03-19 2018-05-01 US Midazolam Injection 5 mg/1mL Intramuscular; Intravenous West-Ward Pharmaceuticals Corp. 2000-06-20 Not applicable US Midazolam Injection, solution 5 mg/1mL Intramuscular; Intravenous Fresenius Kabi 2014-10-03 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Midazolam HCl Midazolam hydrochloride (0.5 mg/1mL) Injection, solution Intravenous Cantrell Drug Company 2014-09-03 Not applicable US Midazolam HCl Midazolam hydrochloride (1 mg/1mL) Injection, solution Intravenous Cantrell Drug Company 2013-06-28 Not applicable US MKO Melt Midazolam (3 mg/1) + Ketamine hydrochloride (25 mg/1) + Ondansetron hydrochloride dihydrate (2 mg/1) Troche Sublingual Imprimis Njof, Llc 2018-12-01 Not applicable US - International/Other Brands
- Anquil (General Pharma) / Benzosed (Pharmaceutical) / Buccolam / Dalam (Richmond) / Damizol (Specifar) / Demizolam (Dem Ilaç) / Doricum (Roche) / Dormicum (Roche) / Dormid (Scott) / Dormipron (Chalver) / Dormire (Cristália) / Dormitol (Square) / Dormixal (Demo) / Dormonid (Roche) / Drimnorth (Northia) / Epistatus (IFET) / Flormidal (Galenika) / Fulsed (Ranbaxy) / Fulsed Injection (Terapia) / Garen (Bio-Pharma) / Gobbizolam (Gobbi) / Hipnazolam (EMS) / Hipnoz (Pharos) / Hypnofast (Incepta) / Hypnovel (Roche) / Ipnovel (Roche) / Nocturna (Lafi) / Setam (Rimsa) / Talentum (Fisiopharma) / Terap (Sanitas) / Versed (Roche)
- Categories
- Adjuvants, Anesthesia
- Anesthetics
- Anti-Anxiety Agents
- Benzodiazepine hypnotics and sedatives
- Benzodiazepines and benzodiazepine derivatives
- Central Nervous System Agents
- Central Nervous System Depressants
- CYP3A Substrates (Sensitive)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- GABA Agents
- GABA Modulators
- Hypnotics and Sedatives
- Nervous System
- Neurotransmitter Agents
- Psycholeptics
- Psychotropic Drugs
- Tranquilizing Agents
- UNII
- R60L0SM5BC
- CAS number
- 59467-70-8
- Weight
- Average: 325.767
Monoisotopic: 325.078203343 - Chemical Formula
- C18H13ClFN3
- InChI Key
- DDLIGBOFAVUZHB-UHFFFAOYSA-N
- InChI
- InChI=1S/C18H13ClFN3/c1-11-21-9-13-10-22-18(14-4-2-3-5-16(14)20)15-8-12(19)6-7-17(15)23(11)13/h2-9H,10H2,1H3
- IUPAC Name
- 12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0²,⁶]tetradeca-1(10),3,5,8,11,13-hexaene
- SMILES
- CC1=NC=C2CN=C(C3=CC=CC=C3F)C3=C(C=CC(Cl)=C3)N12
Pharmacology
- Indication
The midazolam intravenous injection is indicated for preoperative sedation/anxiolysis/anesthesia induction/amnesia [11], and the intramuscular injection is indicated for the treatment of status epilepticus in adults [Label].
Midazolam is also an agent for conscious sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures. It is important to note that various routes may be applicable to different indications. Refer to the "indications" section of this drug entry for more detailed information.
- Associated Conditions
- Associated Therapies
- Pharmacodynamics
General effects
Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepine drugs, include sedative, anxiolytic, amnestic, muscle relaxant, as well as hypnotic activities [11]. Benzodiazepines enhance the inhibitory action of the amino acid neurotransmitter gamma-aminobutyric acid (GABA). Receptors for GABA are targeted by many important drugs that affect GABA function and are commonly used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, and aggressive behavior [7].
Sedation and memory
The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection [Label]. In one study of adults, when tested the following day, 73% of the patients who were administered midazolam intramuscularly had no recollection of memory cards shown 30 minutes following drug administration; 40% had no recollection of the memory cards shown 60 minutes after drug administration. Onset time of sedative effects in pediatric patients begins within 5 minutes and peaks at 15-30 minutes depending upon the dose administered. In the pediatric population, up to 85% had no memory of pictures shown after receiving intramuscular midazolam compared to 5% of the placebo control group [11].
Sedation in both adult and pediatric patients is reached within 3 to 5 minutes post intravenous (IV) injection. The time of onset is affected by the dose administered and the simultaneous administration of narcotic pre-medication. Seventy-one (71%) percent of the adult patients in clinical endoscopy studies had no memory of insertion of the endoscope; 82% of the patients had no memory of withdrawal of the endoscope [Label].
Anesthesia induction
When midazolam is administered intravenously (IV) for anesthetic induction, induction of anesthesia occurs in about 1.5 minutes when narcotic pre-medication has been given and in 2 to 2.5 minutes without narcotic pre-medication/ other sedative pre-medication. Impairment in a memory test was observed in 90% of the patients [Label].
- Mechanism of action
The actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening [11]. These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system [6].
Target Actions Organism AGamma-aminobutyric acid receptor subunit alpha-1 potentiatorHumans AGamma-aminobutyric acid receptor subunit alpha-2 potentiatorHumans AGamma-aminobutyric acid receptor subunit alpha-5 potentiatorHumans AGamma-aminobutyric acid receptor subunit alpha-3 potentiatorHumans AGamma-aminobutyric acid receptor subunit alpha-4 potentiatorHumans AGamma-aminobutyric acid receptor subunit alpha-6 potentiatorHumans - Absorption
Oral Absorption: Rapidly absorbed after oral administration. The absolute bioavailability, if given intramuscularly (IM), is greater than 90% [Label]. Due to first pass metabolism, only 40-50% of the administered oral dose reaches the circulation [6]. The absolute bioavailability of the midazolam syrup in pediatric patients is about 36% [10].
Intramuscular Absorption: The mean peak concentration (Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hour (50% CV)[Label].
Rectal administration: After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50% [12].
Intranasal Administration: Midazolam is absorbed rapidly after intranasal administration. Mean peak plasma concentrations are reached within 10.2 to 12.6 minutes. The bioavailability is between 55 and 57% [12].
- Volume of distribution
Female gender, old age, and obesity may increase the volume of distribution. Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid [Label], [11].
Intravenous administration
1.24 to 2.02 L/kg [pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam] 1 to 3.1 L/kg [midazolam intravenously administered, healthy adults] [11].
Intramuscular administration
The mean apparent volume of distribution of midazolam after a single IM dose of 10 mg midazolam in healthy adults was 2117 (±845.1) mL/kg [Label].
- Protein binding
Midazolam is approximately 97% bound to plasma protein, mainly albumin, in adults. The 1-hydroxy metabolite is approximately 89% bound to plasma protein[11].
- Metabolism
Midazolam is primarily metabolized in the liver and gut by CYP3A4 [Label] to its pharmacologic active metabolite, alpha-hydroxymidazolam (also known as 1-hydroxy-midazolam), and 4-hydroxymidazolam (which makes up 5% or less of the biotransformation products). This metabolite likely contributes to the pharmacological effects of midazolam. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes [6].
- Route of elimination
The α-hydroxymidazolam glucuronide conjugate of midazolam is excreted in urine. No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates. The amount of midazolam excreted unchanged in the urine when given intravenously is less than 0.5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate [11].
Plasma clearance of midazolam is higher in patients that remain in supine position, because of a 40-60 percent increase in hepatic blood flow during supination. Pregnancy may also increase the metabolism of midazolam [6].
- Half life
Intravenous: healthy adults = 1.8 to 6.4 hours (mean of 3 hours) [11].
Intramuscular: Following IM administration of 10 mg midazolam, mean (±SD) elimination half-life was 4.2 (±1.87) hours [Label].
- Clearance
Intramuscular: apparent total body clearance, 367.3 (±73.5) mL/hr/kg [Label]. Intravenous: total clearance (Cl), 0.25 to 0.54 L/hr/kg
- Toxicity
LD50=215 mg/kg, in rats [MSDS].
Overdose
Signs of overdose include sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs. Serious cardiorespiratory adverse reactions have occurred, sometimes ending in death or permanent neurologic effects, after the administration of midazolam [Label].
A note on cardiac and respiratory depression
After administration of midazolam, continuous monitoring of respiratory and cardiac function is recommended until the patient is in stable condition. Serious and life-threatening cardiorespiratory adverse reactions, including hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam. Patients should be monitored in a setting with immediate access to resuscitative drugs if they are required. Resuscitation equipment and personnel trained in their use and skilled in airway management should be available when midazolam is administered [Label].
The usual recommended intramuscular pre-medicating doses of midazolam do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for at least 15 minutes longer than the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more severe in adult patients diagnosed with chronic obstructive pulmonary disease (COPD) [11].
A note on dependence
When midazolam is used in long-term sedation in the ICU (intensive care unit) or other settings, physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment; this risk is also greater in patients with a medical history of substance abuse [9].
Special caution should be exercised when administering midazolam in the following populations [9]: adults over 60 years of age, chronically ill or debilitated patients, which may include patients with chronic respiratory insufficiency, patients with chronic renal failure, impaired hepatic function or with impaired cardiac function, pediatric patients (especially those with cardiovascular instability). These high-risk patients require lower dosages and should be monitored on a continuous basis for early signs of alterations of vital functions, so that appropriate management may be administered.
Mutagenesis
Midazolam was negative for genotoxicity during in vitro and in vivo assays [Label].
Impairment of Fertility
When midazolam (0, 1, 4, or 16 mg/kg) was given orally to male and female rats before and during mating and continuing in females throughout gestation and lactation, no adverse effects on male or female fertility were observed. Midazolam plasma exposures (AUC) at the highest dose tested were approximately 6 times that in humans at the recomended human dose [Label].
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction (R)-warfarin The metabolism of Midazolam can be decreased when combined with (R)-warfarin. (S)-Warfarin The metabolism of Midazolam can be decreased when combined with (S)-Warfarin. 3-isobutyl-1-methyl-7H-xanthine The therapeutic efficacy of Midazolam can be decreased when used in combination with 3-isobutyl-1-methyl-7H-xanthine. 3,4-Methylenedioxyamphetamine The risk or severity of adverse effects can be increased when Midazolam is combined with 3,4-Methylenedioxyamphetamine. 3,5-diiodothyropropionic acid The metabolism of Midazolam can be decreased when combined with 3,5-diiodothyropropionic acid. 4-Bromo-2,5-dimethoxyamphetamine The risk or severity of adverse effects can be increased when Midazolam is combined with 4-Bromo-2,5-dimethoxyamphetamine. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Midazolam. 4-Methoxyamphetamine The risk or severity of adverse effects can be increased when Midazolam is combined with 4-Methoxyamphetamine. 5-androstenedione The metabolism of Midazolam can be decreased when combined with 5-androstenedione. 6-Deoxyerythronolide B The serum concentration of Midazolam can be increased when it is combined with 6-Deoxyerythronolide B. - Food Interactions
- Grapefruit juice slows the product's absorption and significantly increases its bioavailability.
References
- Synthesis Reference
- US6262260
- General References
- Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. [PubMed:6135616]
- Isojarvi JI, Tokola RA: Benzodiazepines in the treatment of epilepsy in people with intellectual disability. J Intellect Disabil Res. 1998 Dec;42 Suppl 1:80-92. [PubMed:10030438]
- Garratt JC, Gent JP, Feely M, Haigh JR: Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? Eur J Pharmacol. 1988 Jan 5;145(1):75-80. [PubMed:2894998]
- Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. [PubMed:17287588]
- Vermeeren A: Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18(5):297-328. [PubMed:15089115]
- Nordt SP, Clark RF: Midazolam: a review of therapeutic uses and toxicity. J Emerg Med. 1997 May-Jun;15(3):357-65. [PubMed:9258787]
- Jembrek MJ, Vlainic J: GABA Receptors: Pharmacological Potential and Pitfalls. Curr Pharm Des. 2015;21(34):4943-59. [PubMed:26365137]
- Siegel GJ, Agranoff BW, Albers RW et al. (1999). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott Williams.
- Drug Scheduling: United States Drug Enforcement Administration (DEA) [Link]
- DailyMed: Midazolam [Link]
- Intravenous Midazolam FDA label [File]
- MedSafe NZ: Midazolam Inj [File]
- External Links
- Human Metabolome Database
- HMDB0014821
- KEGG Drug
- D00550
- KEGG Compound
- C07524
- PubChem Compound
- 4192
- PubChem Substance
- 46507611
- BindingDB
- 21363
- ChEBI
- 6931
- ChEMBL
- CHEMBL655
- Therapeutic Targets Database
- DAP000241
- PharmGKB
- PA450496
- IUPHAR
- 3342
- Guide to Pharmacology
- GtP Drug Page
- HET
- 08J
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Midazolam
- ATC Codes
- N05CD08 — Midazolam
- AHFS Codes
- 28:24.08 — Benzodiazepines
- PDB Entries
- 3u5k / 5te8
- FDA label
- Download (250 KB)
- MSDS
- Download (68.9 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Apothecon inc div bristol myers squibb
- App pharmaceuticals llc
- Astrazeneca pharmaceuticals lp
- Baxter healthcare corp anesthesia and critical care
- Baxter healthcare corp anesthesia critical care
- Bedford laboratories div ben venue laboratories inc
- Ben venue laboratories inc
- Claris lifesciences ltd
- Hospira inc
- International medicated systems ltd
- International medication systems ltd
- Taylor pharmaceuticals
- Wockhardt ltd
- Hlr technology
- Apotex inc richmond hill
- Hi tech pharmacal co inc
- Paddock laboratories inc
- Ranbaxy laboratories ltd
- Roxane laboratories inc
- Hoffmann la roche inc
- Packagers
- Akorn Inc.
- APP Pharmaceuticals
- A-S Medication Solutions LLC
- B&B Pharmaceuticals
- Baxter International Inc.
- Bedford Labs
- Ben Venue Laboratories Inc.
- Cardinal Health
- Cura Pharmaceutical Co. Inc.
- Dispensing Solutions
- Ebewe Pharma
- Hi Tech Pharmacal Co. Inc.
- Hospira Inc.
- Mikart Inc.
- Novex Pharma
- Paddock Labs
- Patheon Inc.
- Pharmedium
- Physicians Total Care Inc.
- Ranbaxy Laboratories
- Roxane Labs
- Wockhardt Ltd.
- Dosage forms
Form Route Strength Liquid Intramuscular; Intravenous 1 mg Liquid Intramuscular; Intravenous 5 mg Solution Buccal 10 mg Solution Buccal 2.5 mg Solution Buccal 5 mg Solution Buccal 7.5 mg Injection, solution Intramuscular; Intravenous 10 mg/2mL Injection, solution Intramuscular; Intravenous 2 mg/2mL Injection, solution Intravenous 0.5 mg/1mL Injection, solution Intravenous 1 mg/1mL Injection Intramuscular; Intravenous 1 mg/1mL Injection Intramuscular; Intravenous 10 mg/2mL Injection Intramuscular; Intravenous 2 mg/2mL Injection Intramuscular; Intravenous 5 mg/1mL Injection, solution Intramuscular; Intravenous 1 mg/1mL Injection, solution Intramuscular; Intravenous 5 mg/1mL Syrup Oral 10 mg/5mL Syrup Oral 2 mg/1mL Solution Intramuscular; Intravenous 1 mg Solution Intramuscular; Intravenous 5 mg Troche Sublingual Injection, solution Intramuscular 5 mg/1mL - Prices
Unit description Cost Unit Midazolam 5 mg/ml 3.9USD ml Midazolam-nacl 2 mg/ml inj 2.31USD ml Midazolam hcl 5 mg/ml vial 1.18USD ml Midazolam-nacl 1 mg/ml inj 1.13USD ml Midazolam hcl 2 mg/ml syrup 1.08USD ml Midazolam 1 mg/ml isecure syr 0.73USD ml Midazolam hcl 1 mg/ml vial 0.26USD ml DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 161-164 MSDS boiling point (°C) 497 MSDS water solubility soluble FDA label - Predicted Properties
Property Value Source Water Solubility 0.00987 mg/mL ALOGPS logP 3.89 ALOGPS logP 3.33 ChemAxon logS -4.5 ALOGPS pKa (Strongest Basic) 6.57 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 30.18 Å2 ChemAxon Rotatable Bond Count 1 ChemAxon Refractivity 99.43 m3·mol-1 ChemAxon Polarizability 32.7 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9724 Caco-2 permeable + 0.8866 P-glycoprotein substrate Non-substrate 0.5074 P-glycoprotein inhibitor I Inhibitor 0.5587 P-glycoprotein inhibitor II Inhibitor 0.8388 Renal organic cation transporter Inhibitor 0.7476 CYP450 2C9 substrate Non-substrate 0.7366 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Substrate 0.7194 CYP450 1A2 substrate Inhibitor 0.8586 CYP450 2C9 inhibitor Inhibitor 0.7132 CYP450 2D6 inhibitor Non-inhibitor 0.6887 CYP450 2C19 inhibitor Inhibitor 0.6554 CYP450 3A4 inhibitor Non-inhibitor 0.5214 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9001 Ames test Non AMES toxic 0.8024 Carcinogenicity Non-carcinogens 0.7703 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 3.1488 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9827 hERG inhibition (predictor II) Non-inhibitor 0.7379
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as imidazo[1,5-a][1,4]benzodiazepines. These are compounds containing an imidazole ring and a 1,4-benzodiazepine ring system, both sharing one nitrogen atom.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzodiazepines
- Sub Class
- 1,4-benzodiazepines
- Direct Parent
- Imidazo[1,5-a][1,4]benzodiazepines
- Alternative Parents
- Fluorobenzenes / 1,4-diazepines / N-substituted imidazoles / Aryl fluorides / Aryl chlorides / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds show 3 more
- Substituents
- Imidazo[1,5-a][1,4]benzodiazepine / Para-diazepine / Fluorobenzene / Halobenzene / Aryl chloride / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Benzenoid / N-substituted imidazole show 16 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- diazepine (CHEBI:6931)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
- Gene Name
- GABRA1
- Uniprot ID
- P14867
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-1
- Molecular Weight
- 51801.395 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Haefely W: Benzodiazepine interactions with GABA receptors. Neurosci Lett. 1984 Jun 29;47(3):201-6. [PubMed:6147796]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
- Gene Name
- GABRA2
- Uniprot ID
- P47869
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-2
- Molecular Weight
- 51325.85 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Transporter activity
- Specific Function
- GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
- Gene Name
- GABRA5
- Uniprot ID
- P31644
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-5
- Molecular Weight
- 52145.645 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
- Gene Name
- GABRA3
- Uniprot ID
- P34903
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-3
- Molecular Weight
- 55164.055 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
- Gene Name
- GABRA4
- Uniprot ID
- P48169
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-4
- Molecular Weight
- 61622.645 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Potentiator
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
- Gene Name
- GABRA6
- Uniprot ID
- Q16445
- Uniprot Name
- Gamma-aminobutyric acid receptor subunit alpha-6
- Molecular Weight
- 51023.69 Da
References
- Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
- Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
- Tan KR, Rudolph U, Luscher C: Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97. doi: 10.1016/j.tins.2011.01.004. Epub 2011 Feb 25. [PubMed:21353710]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Foti RS, Rock DA, Wienkers LC, Wahlstrom JL: Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos. 2010 Jun;38(6):981-7. doi: 10.1124/dmd.110.032094. Epub 2010 Mar 4. [PubMed:20203109]
- Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H: Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica. 1998 Dec;28(12):1203-53. [PubMed:9890159]
- Zhou S, Chan E, Lim LY, Boelsterli UA, Li SC, Wang J, Zhang Q, Huang M, Xu A: Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab. 2004 Oct;5(5):415-42. [PubMed:15544435]
- Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, Wrighton SA: Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002 Aug;30(8):883-91. [PubMed:12124305]
- Galetin A, Clarke SE, Houston JB: Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos. 2002 Dec;30(12):1512-22. [PubMed:12433827]
- Obach RS, Reed-Hagen AE: Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos. 2002 Jul;30(7):831-7. [PubMed:12065442]
- Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Patki KC, Von Moltke LL, Greenblatt DJ: In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos. 2003 Jul;31(7):938-44. [PubMed:12814972]
- Wandel C, Bocker R, Bohrer H, Browne A, Rugheimer E, Martin E: Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesth. 1994 Nov;73(5):658-61. [PubMed:7826796]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Protein homodimerization activity
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A4
- Uniprot ID
- P22310
- Uniprot Name
- UDP-glucuronosyltransferase 1-4
- Molecular Weight
- 60024.535 Da
References
- Klieber S, Hugla S, Ngo R, Arabeyre-Fabre C, Meunier V, Sadoun F, Fedeli O, Rival M, Bourrie M, Guillou F, Maurel P, Fabre G: Contribution of the N-glucuronidation pathway to the overall in vitro metabolic clearance of midazolam in humans. Drug Metab Dispos. 2008 May;36(5):851-62. doi: 10.1124/dmd.107.019539. Epub 2008 Feb 6. [PubMed:18256203]
- Hyland R, Osborne T, Payne A, Kempshall S, Logan YR, Ezzeddine K, Jones B: In vitro and in vivo glucuronidation of midazolam in humans. Br J Clin Pharmacol. 2009 Apr;67(4):445-54. doi: 10.1111/j.1365-2125.2009.03386.x. [PubMed:19371318]
- Seo KA, Bae SK, Choi YK, Choi CS, Liu KH, Shin JG: Metabolism of 1'- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. Drug Metab Dispos. 2010 Nov;38(11):2007-13. doi: 10.1124/dmd.110.035295. Epub 2010 Aug 16. [PubMed:20713656]
- Liu Y, She M, Wu Z, Dai R: The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors. J Enzyme Inhib Med Chem. 2011 Jun;26(3):386-93. doi: 10.3109/14756366.2010.518965. Epub 2010 Oct 13. [PubMed:20939765]
Drug created on June 13, 2005 07:24 / Updated on February 18, 2019 20:23