Lorazepam glucuronide

Valproate Lorazepam -fr 20% increase in lorazepam AUC, 31% decrease in formation CL of lorazepam glucuronide 40% decrease in lorazepam CL 148,149... 

Gas Chromatography-Mass Spectrometry. In plasma or urine lorazepam and lorazepam glucuronide, limit of detection 2ng/ml—S. Higuchi et al., J. Chromat., 1979, 164 Biomed. Appl., 6, 55-61. 

Therapeutic Concentration. In plasma, usually in the range 0.05 to 0.24pg/ml. Lorazepam glucuronide accumulates in plasma achieving concentrations greater than those of unchanged drug. 

Following daily oral doses of 6 mg to 8 subjects, mean steady-state plasma concentrations of 0.09 pg/ml of lorazepam and 0.17 pg/ml of lorazepam glucuronide were reported in 7 subjects receiving 10 mg daily, the mean steady-state plasma concentrations were 0.16 and 0.27 pg/ml respectively (D. J. Greenblattet fl/., 7. din. Pharmac., 1977,17,495-500). 

Half-life. Plasma half-life, lorazepam 9 to 24 hours (mean 14), lorazepam glucuronide about 16 hours. 

Disposition in the Body. Well absorbed after oral administration bioavailability about 80%. Metabolised to some extent by N-demethylation to lorazepam. About 80% of a dose is excreted in the urine as lormetazepam glucuronide in 72 hours, and about 6% as lorazepam glucuronide. 

Lorazepam (Ativan) muscle relaxation preanesthetic medication Anxiety preanesthetic 8-25 Lorazepam glucuronide... 

Elimination of lorazepam occurs by metabolism within the hver and renal excretion of the metabolites. Glucuronidation to form lorazepam-glucuronide is the major pathway for metabolism. Minor metabolites include a hydroxylated derivative, a quinazolinone derivative and a quinazoline carboxylic acid. Seventy... 

In contrast to chlordiazepoxide and diazepam, lorazepam and oxazepam are not metabolized into active compounds in the liver. Instead, they are excreted by the kidneys following glucuronidation. This is important because many alcohol-dependent patients have compromised liver function. Therefore, when treatment is initiated before the results of blood tests for liver function are known, as is often the case in outpatient clinics, lorazepam and oxazepam may be preferred. Patients with liver disease may still be treated with diazepam and chlordiazepoxide, but at lower doses. This can be accommodated with the loading technique, although hourly dosing with 5 mg of diazepam or 25 mg of chlordiazepoxide may be sufficient. 

Does not include agents metabolized by glucuronidation (lorazepam, oxazepam, temazepam). 

Both temazepam and lorazepam undergo glucuronidation. The clearance rates for these compounds are lower in women (Divoll et al. 1981 D. J. Greenblatt et al. 1980 R. B. Smith et al. 1983). This is the direction predicted based on animal models (Skett 1988). OCs have been shown to increase the rate of these reactions, and one would expect the elimination half-lives to be briefer in women who are using OCs. In fact, the elimination half-life does decrease in women who take OCs (Patwardhan et al. 1983 Stoehr et al. 1984). 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relationship to the time course of pharmacologic effects. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22-1. 

Abemethy DR, Greenblatt DJ, Divoll M, et al. Enhanced glucuronide conjugation of drugs in obesity studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin... 

Abemethy DR, Greenblatt DJ, Ameer B, et al. Probenecid impairment of acetaminophen and lorazepam clearance direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther 1985 234(2) 345-349. 

Benzodiazepine and azapirone derivatives are widely used drugs in this class, and most are metabolized extensively by enzymes of the CYP3A family, except oxazepam, lorazepam, and temazepam, which are mostly glucuronidated (52). Again, several studies have shown that inducers and inhibitors of CYP3A can markedly alter plasma concentrations of many of these drugs, but in only a few cases have toxic effects, such as deep unconsciousness, been reported (19,52,53). Nonetheless, patients on these drugs should probably be monitored carefully, particularly the elderly, who may suffer severe physical injury as a result of falls from impairment of psychomotor function. 

FLUOXETINE, FLUVOXAMINE, PAROXETINE BZDs - ALPRAZOLAM, DIAZEPAM, MIDAZOLAM t in plasma concentrations of these BZDs. Likely t sedation and interference with psychomotor activity Alprazolam, diazepam and midazolam are subject to metabolism by CYP3A4. Fluvoxamine, fluoxetine and possibly paroxetine are inhibitors of CYP3A4 sertraline is a weak inhibitor. SSRIs are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor Warn patients about risks associated with activities that require alertness. Consider use of alternatives such as oxazepam, lorazepam and temazepam, which are metabolized by glucuronidation >- For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression... 

Lorazepam (4) is well absorbed, with oral bioavailabilty close to 100% after a typical 2 mg dose, and peak levels are obtained within 2h of administration. Lorazepam is conjugated at the 3-hydroxy group and the resulting inactive glucuronide is excreted in the urine with a mean elimination half-life of approximately 14 h (82). 

Oxazepam (6) is formed during the metabolism of many other benzodiazepines, but its own metabolic profile is relatively simple. Like lorazepam, the major metabolic pathway is glucuronidation at the 3-hydroxy group followed by urinary excretion. Up to 80% of the dose is recovered from the urine as the glucuronide. The mean half-life of oxazepam is approximately 9 h (98). 

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