Chemical formula: C₁₄H₁₀BrN₃O Molecular mass: 316.153 g/mol PubChem compound: 2441
Bromazepam is a pyridylbenzodiazepine compound with anxiolytic properties.
Bromazepam is rapidly absorbed from the gastro-intestinal tract and reaches peak plasma concentrations within 2 hours of oral administration. The absolute bioavailability of bromazepam from the tablet is 60%.
Food may decrease the bioavailability of bromazepam, however, the clinical relevance of this has not been established. During multiple dosing of bromazepam the extent of absorption remains constant; predictable steadystate concentrations are observed and confirm linear kinetics for the drug. Steady state plasma concentrations are reached in around 5–9 days. Following multiple oral doses of 3 mg given three times daily, the average maximum concentration of bromazepam at steady-state was 120 ng/mL which is 3- to 4- fold higher than that observed after a single 3 mg dose.
After absorption, bromazepam is rapidly distributed in the body. On average, 70% of bromazepam is bound by hydrophobic interaction to plasma proteins; binding partners are albumin and α1-acid glycoprotein. The volume of distribution is around 50 liters.
Bromazepam is extensively metabolised in the liver. No metabolites with a half-life longer than that of the parent drug are formed. Quantitatively, two metabolites dominate, 3-hydroxy-bromazepam (less active than bromazepam) and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine (inactive). Metabolites of bromazepam do not contribute significantly to the effects of the drug.
Bromazepam is metabolized, at least in part, through cytochrome P450 (CYP450). However, the specific CYP isozymes involved have not been identified. Nevertheless, the observations that a strong CYP3A4 inhibitor (itraconazole) and a moderate CYP2C9 inhibitor (fluconazole) had no effect on the pharmacokinetics of bromazepam suggest that these isozymes are not involved to a major extent. The pronounced interaction with fluvoxamine points to co-involvement of CYP1A2.
Bromazepam has an elimination half-life of about 20 hours and an elimination clearance of around 40ml/min.
Metabolism is the key elimination pathway for the drug. The urinary recovery of intact bromazepam is only 2% and of the glucuronide conjugates of 3- hydroxy-bromazepam and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine are 27% and 40% of the administered dose respectively.
Older people may have significantly higher peak concentrations, a smaller volume distribution, increased serum free fraction, lower clearance and hence also a prolonged elimination half-life. This indicates that steady-state concentrations of bromazepam at any given dosing rate will be on average nearly twice as high in an elderly subject as compared to a younger individual.
The pharmacological effects of benzodiazepines appear to be greater in elderly patients than in younger patients, even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function. A reduction in dose for elderly patients is recommended.
No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with renal impairment.
No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with hepatic impairment.
Carcinogenicity studies conducted in rats did not reveal any evidence of a carcinogenic potential for bromazepam.
Bromazepam was not genotoxic in in-vitro and in-vivo tests.
Daily oral administration of bromazepam did not have any effect on the fertility and general reproductive performance of rats.
Increases in fetal mortality, an increase in the stillbirth rate and a reduction in pup survival have been observed when bromazepam was given to pregnant rats. In studies on embryotoxicity/teratogenicity no teratogenic effect was detected up to a dosage of 125 mg/kg/day.
Following oral administration with doses of up to 50 mg/kg/day to pregnant rabbits a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorptions have been observed.
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