Oxazepam Research Articles

Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog

Diazepam (DZ) was used as a substrate in drug metabolism studies to characterise the differences in metabolite profiles in hepatocytes isolated from four species: Wistar rat, cynomolgus monkey, beagle dog and man. Hepatocytes were incubated with DZ (20 μM) for 180 min at 3 hr post isolation in culture, and the disappearance of parent compound and appearance of its metabolites determined. DZ disappearance was found to be monoexponential in rat, monkey and human cells, but that DZ disappearance in dog hepatocytes was best described by a two compartment process. There were considerable differences in both the rates of formation and the profiles of metabolites produced from DZ in each species. Drug metabolism of DZ was determined in five human hepatocyte preparations. The rates of formation of both the major metabolites, temezepam (TEM) and nordiazepam (NOR) were highly variable between samples, and oxazepam (OX) was detected in only three of the preparations. There was no evidence of further metabolism of these metabolites, and the profiles were comparable with in vivo findings. In a single case, human hepatocytes were cultured for five days, and DZ was used as substrate to characterise the changes in drug metabolising activities. There was a rapid loss in the production of OX in the initial 24 hr, and a complete loss of 3-hydroxylation activities in the succeeding 120 hr. N-demethylation activities, however, were well maintained, and the appearance of NOR declined to 47% of initial rate. The hepatocytes of all species were found to produce NOR and TEM as metabolites; NOR representing the principal metabolite in the dog, monkey and human cells. In the dog, TEM was found only as a minor metabolite. OX was a significant metabolite in the monkey and a minor metabolite in the dog and human hepatocytes, but was not detected in rat cultures. The principal metabolite in rat cells was 4'-hydroxy diazepam, which was rapidly further metabolised to its glucuronide. The drug metabolising activities of the hepatocyte cultures towards DZ were comparable with the drug metabolism of DZ found in vivo in each species. These findings substantiate hepatocytes as an in vitro model of hepatic metabolism.

Flunitrazepam or Oxazepam for Premedication and Sedation?

Flunitrazepam or Oxazepam for Premedication and Sedation?

Promoting effect of oxazepam in rat hepatocarcinogenesis.

In order to check whether the benzodiazepine, oxazepam (OZ), has a modulating effect on the development of liver cancer, it was given to rats previously submitted to two different protocols of hepatocarcinogenesis: the resistant hepatocyte protocol and Pitot's model (initiation-promotion). Its effects were compared with those of phenobarbital (PB) administered under the same conditions. As compared with basal diet, a diet containing 0.05% of PB and 0.1% of OZ enhanced, in both models, the development of gamma-glutamyltransferase-positive lesions in early stages. OZ also had a promoting effect on the development of liver cancers in later stages in both models whereas PB only enhanced it in the resistant hepatocyte protocol. Thus, like PB, OZ may have a promoting effect on liver cancer in rats.

Oxazepam as a Presurgical Hypnotic in Gynaecology

Oxazepam as a Presurgical Hypnotic in Gynaecology

Relation between time courses of pharmacological effects and of plasma levels of camazepam and its active metabolites in rats.

Camazepam (CZ), a benzodiazepine, was biotransformed to more than ten metabolites. After intravenous and oral administration of these metabolites to rats, CZ, tempazepam (TZ), oxazepam (OZ), and hydroxy CZ (M5) were found to possess pharmacological activities. The brain-to-plasma concentration ratios of CZ and these active metabolites were essentially constant with time after oral administration of CZ. Thus the brain, target organ, was kinetically included in the plasma compartment. The extent of binding of these compounds to plasma protein was independent of concentration tested. Plasma levels of an unchanged drug and its active metabolite(s), and muscle relaxation effect (the impairment of rota rod performance) were measured at 0.5 to 8 h after oral administration of 2 to 3 doses of CZ, TZ, and OZ to rats. When the effect and plasma level data were computer-fitted to a simple Hill equation or a modified Hill equation including competitive factors, the modified Hill equation was found to be adequately applicable to the concentration-effect relation. The parameter values thus obtained could predict the contribution of the administered drug and its active metabolite(s) to the observed pharmacological effect after administration.

Prenatal diazepam: distribution and metabolism in perinatal rats.

Previous investigations have revealed that prenatal exposure to diazepam (DZ) alters brain development and behavior in the offspring of rats and mice. In order to understand how DZ may affect the developing nervous system it is necessary to examine its metabolic fate in the neonate. It is therefore the aim of this study to investigate the disposition, metabolism, and persistence of DZ in the neonate. Dams were injected s.c. with 2.5 mg/kg of 14C DZ (10 muCi/day) on days 13-20 of gestation and their litters were fostered at birth. Dams killed within 24 hours postpartum and neonates killed at postnatal days 0, 10, and 20 were analyzed for 14C activity. Brain levels (pmoles DZ and metabolites/100 mg tissue SE) were 3.4 +/- 0.3 in the dam and in the neonates were 3.2 +/- 0.3 (day 0), 3.4 +/- 0.3 (day 10), and undetectable at day 20. Neonatal peripheral tissue 14C activity was undetectable by day 10. Brain regional analysis indicates 14C is highest in the colliculi at day 0, but not at day 10. Brain levels of DZ, oxazepam (OXA), N-desmethyldiazepam (NDZ), and the glucuronide (GLU) determined by high-performance liquid chromatography (HPLC), were GLU (49%), DZ (28%), and NDZ (24%) in the dam; GLU (52%), DZ (24%), and NDZ (25%) in the day 0 neonate; and GLU (32%), DZ (12%), NDZ (39%), and OXA (19%) at day 10. The distribution and metabolism of 14C DZ that persists in the neonate following prenatal exposure differs from that which occurs in the dam.(ABSTRACT TRUNCATED AT 250 WORDS)

Driving under the influence of Oxazepam: Guilt without Responsability

Driving under the influence of Oxazepam: Guilt without Responsability

Identification of oxaxepam and lorazepam glucuronides by chemical ionization mass spectrometry.

Die Glucuronide des Oxazepams und Lorazepams wurden aus dem Harn von Zwergschweinen, denen die entsprechenden Benzodiazepine verabreicht wurden, isoliert. Die Metaboliten wurden durch Analyse der Spaltprodukte gekennzeichnet. Massenspektrometrie der Trimethylsilylderavite war fur die Struktur derO-Glucuronide beweisend.

Diazepam elimination in premature and full term infants, and children.

Summary Benzodiazepines are often used during labor, and they arealso frequently administered to newborns in cases ofseizure. In adults this class of drug requires an extensivemetabolization in order to be eliminated.The physiological elimination of diazepam admi-nistered at the dose of 0.3 mg/kg by intramuscular route(Tab. I), was followed up in three groups of subjects{premature infants, full-term infants and children). Plasma levels of diazepam (DZ) and of its major metaboliteN-demethyldiazepam (NDZ) could be followed up for48 hours after drug administration in 4 premature infantsand 4 children. 24 hour urinary excretion of DZ, NDZ, N-Methyl-oxazepam (MeOX) and Oxazepam (OX) was followed upin 7 premature infants, 8 full term infants and 5 children.Determination of benzodiazepine compounds both inplasma and urine, was performed, after etheral extraction,by GLC-ECD. In the urine samples free and conjugatedcompounds were measured (Tab. HD.The apparent disappearance rate of diazepam plasma wassignificantly reduced

Oxazepam poisoning in a child

Oxazepam poisoning in a child