Oxazepam
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Mechanism of action
Like other benzodiazepines, oxazepam exerts its anxiolytic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain. GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy. Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased.
The inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), acts on GABAA receptors to regulate vigilance, anxiety, muscle tension, epileptogenic activity and memory functions. Benzodiazepines modulate GABA-evoked chloride currents through a binding site on the GABAA receptor-operated chloride channel. GABA agonists and benzodiazepine agonists simultaneously enhance the binding of the other to its receptor. Benzodiazepine binding appears to shift the GABA receptor from a low affinity state to a high affinity state and also stabilizes the receptor in a conformation that permits the ion channel to remain open. Similarly, GABA binding also enhances benzodiazepine agonist binding to its receptor via the same mechanism. Thus, GABA receptor agonist and benzodiazepine receptor agonists are positive allosteric effectors for each other.
The exact sites and mode of action of the benzodiazepines are unknown. The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. The effects of benzodiazepines may be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid. Benzodiazepines are capable of producing all levels of CNS depression from mild sedation to hypnosis to coma. /Benzodiazepines/
Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid eye movement sleep. Rapid eye movement rebound does not occur when the drugs are withdrawn. Stage 3 and 4 sleep are markedly reduced by usual doses of the drugs; the clinical importance of these sleep stage alterations has not been established. /Benzodiazepines/
Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking exitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function. /Benzodiazepines/
Pharmacodynamics
Benzodiazepines, including oxazepam, exert their sedative and anxiolytic effects by potentiating the effects of endogenous GABA, the primary inhibitory neurotransmitter in the CNS. Compared to other benzodiazepines, it has relatively low potency and a moderate duration of action. Oxazepam should be administered with caution to patients for whom a drop in blood pressure may lead to cardiac complications as, in rare cases, it may cause hypotension.
Pharmacokinetics
Half-life
The mean elimination half-life of oxazepam is 8.2 hours.
Considerable variation in the elimination half life has been reported, with mean values ranging from about 5 to about 15 hr. Values of 6.7 hr (range, 5.5-9.2 hr) and 5.8 hr (range, 5.4- 8.4 hr) /were found/ following intravenous and oral administration, respectively. A sex difference has been reported, with a value of 7.8 +/- 0.4 hr (range, 4.9-10.8 hr) in men and 9.7 +/- 0.8 hr (range, 6.3-19.4 hr) in women.
Elimination half-life of oxazepam is 3-21 hr. /From table/
Absorption
Following oral administration, peak plasma levels (Cmax) averaged 450 mg/mL and occurred approximately 3 hours (Tmax) after dosing.
Oxazepam is primarily eliminated in the urine as its glucuronide metabolite, with the feces containing approximately 21% of the unchanged drug. The majority of an orally ingested dose of oxazepam is excreted within 48 hours.
The miniature swine (like humans) eliminated oxazepam primarily as the glucuronides, while aromatic hydroxylation predominated in the rat. In rats, 70.7 +/- 6.0% of a single oral dose of 20 mg/kg bw was eliminated in feces following biliary secretion, while 18.9 +/- 2.4% of the dose was found in the urine. In CD-1 mice given an oral dose of 22 mg/kg bw oxazepam, 57.8% was recovered from the feces and 27.3% was recovered from urine over five days. ... Treatment with 2500 mg/kg diet (ppm) oxazepam in the diet for 14 days before administration of oxazepam by gastric instillation led to a shift from fecal to urinary excretion in mice, but not rats, so that the urinary excretion almost doubled.
Oxazepam accumulates in adipose tissue. /It was/ found that adipose tissue/blood ratios of the drug in mice given 5 mg/kg bw intravenously varied from 1.7 (at 5 min) to 4.9 (at 30 min). Accumulation also occurred in the brain. Maximal concentrations of oxazepam in the brain were 14.3 +/- 0.17 ug/g in mice, 4.5 +/- 0.03 ug/g in rats and 3.5 +/- 0.47 ug/g in guinea-pigs, all at 5 min. Brain/blood drug level ratios in these species varied from 1.1 (at 1 min) to 11.3 (at 10 hr) in mice, from 1.9 (at 1 min) to 6.2 (at 1 hr) in rats and from 1.9 (at 5 min) to 8.9 (at 5 hr) in guinea-pigs.
/It was/ found that the time of maximum absorption of 30 mg oxazepam was 2.2 hr (range, 0.75-4.25 hr) in 18 men and 3.1 hr (range, 0.5-8.0 hr) in 20 women. The maximal plasma concentrations in this study were 622 +/- 37 ng/mL in men and 837 +/- 51 ng/mL in women.
Oxazepam is absorbed fairly rapidly, reaching peak plasma concentrations within 1-4 hr, with a mean of about 2 hr in most studies.
Metabolism
Oxazepam has a single major inactive metabolite, a glucuronide conjugate. The glucuronidation of the S-isomer is catalyzed by UGT2B15. The glucuronidation of the R-isomer is catalyzed by UGT2B7 and UGT1A9.
The metabolism and the anticonvulsant effect of clorazepate were followed for 2 h after its i.v. administration to mice. The ED50 of the drug was 12 mg/kg at 1 min against pentetrazole-induced convulsions (45 mg/kg i.v.), it reached a minimum at 1 hr (2.0 mg/kg) and rose to 2.7 mg/kg at 2 h. The concentrations of unchanged clorazepate and its metabolites, desmethyldiazepam and oxazepam, were determined in plasma and brain after administration of the respective ED50s. Unchanged clorazepate could be detected in plasma for the first hour but never in brain, so it can be considered as inactive pro-drug. The brain concentrations of desmethyldiazepam and oxazepam after the respective ED50s of clorazepate were considerably higher at 1 and 15 min than after longer time intervals. This may be explained by a time lag needed to reach and bind to the benzodiazepine receptor.
... Oxazepam ... /is/ metabolized by direct conjugation with glucuronic acid.
Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. However, the molecular basis for this phenomenon is currently unknown. We have previously shown that S-oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor Roxazepam glucuronide is produced by multiple UGTs other than UGT2B15. Phenotype-genotype studies were conducted using microsomes and DNA prepared from the same set of 54 human livers. Sequencing of the UGT2B15 gene revealed three nonsynonymous polymorphisms, D85Y, T352I, and K523T, with variant allele frequencies of 0.56, 0.02, and 0.40, respectively. D85Y genotype showed a significant effect (p = 0.012) on S-oxazepam glucuronidation with lower median activities in 85Y/Y livers (49 pmol/min/mg protein) compared with 85D/D livers (131 pmol/min/mg), whereas 85D/Y livers were intermediate in activity (65 pmol/min/mg). There was also a significant trend (p = 0.049) for higher S-oxazepam activities in the two 352T/I livers (135 and 210 pmol/min/mg) compared with the remaining 352T/T livers (median, 64 pmol/min/mg). Conversely, K523T genotype had no apparent effect on oxazepam glucuronidation (p > 0.05). Donor gender also significantly influenced S-oxazepam glucuronidation with higher median activities in male (65 pmol/min/mg) compared with female (39 pmol/min/ mg) livers (p = 0.042). R-Oxazepam glucuronidation was not affected by either genotype or gender (p > 0.05). In conclusion, gender and D85Y genotype are identified as major determinants of S-oxazepam glucuronidation by human liver and may explain in part polymorphic oxazepam glucuronidation by human subjects.
There are three major pathways of oxazepam metabolism in mice and rats (as in humans): direct conjugation, phenyl ring oxidation and diazepine ring contraction. In mice, conjugation is mainly with glucuronide, predominantly excreted in the urine; in rats, conjugation is mainly with sulfate, which is almost entirely eliminated in the feces. The sulfate conjugate of oxazepam, which is unstable in acidic media, may be the source of the fecal oxazepam It has not been detected in mice. Studies with recirculating, perfused male Swiss (CD-1) mouse liver preparations showed that oxazepam glucuronides are the dominant liver metabolites in this species. Oxazepam can also be conjugated with glucuronide by the placenta of rabbits, apparently in contrast to the human organ. Phenyl ring oxidation is more important in rats than in mice (or humans) and a dihydrodiol (probably the 3',4'- dihydrodiol, since 2'-hydroxy derivatives are not known) accounts for about 30% of the 72-hr urinary metabolites in Fischer 344 rats. This metabolite, which probably forms via an arene oxide intermediate and has not been found in mice, holds implications for the toxicological properties of oxazepam. In rats, ring contraction to 6-chloro-4-phenyl- 2(1H)-quinazoline carboxylic acid occurs to roughly one half of the extent seen in mice.
A method for the extraction of diazepam and its metabolites (nordiazepam, temazepam, and oxazepam) from equine urine and serum and their quantitation and confirmation by liquid chromatography-tandem mass spectrometry is presented. Valium, a formulation of diazepam, was administered at a dose of 10 mg intramuscularly to four standard-bred mares. Diazepam is extensively metabolized in the horse to nordiazepam, temazepam, and oxazepam. Diazepam urinary concentrations were found to be less than 6 ng/mL. Nordiazepam was found to be mainly in its glucuronide-conjugated form and was measured out to a collection time of 53-55 hr. Oxazepam and temazepam were entirely conjugated, and their urinary concentrations were measured out to collection times of 121 hr and 77-79 hr, respectively. Diazepam and nordiazepam were measured in equine postadministration serum out to collection times of 6 and 54 hr, respectively. Oxazepam and temazepam were not detected in postadministration serum.
Protein binding
Plasma protein binding is approximately 89%, likely to albumin.
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