Metabolism oxazepam glucuronide

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

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... 

Cimetidine inhibits the liver enzymes associated with oxidative metabolism. Hence, the serum levels of most benzodiazepines affected by this metabolic pathway (aiprazoiam, diazepam, cbiordiazepoxide, fiurazepam, nitrazepam, and triazoiam) were found to be increased when cimetidine was co-administered. Benzodiazepines metabolized by glucuronide conjugation (iorazepam, oxazepam, and temazepam) are not affected by cimetidine. Ranitidine probably has no significant interaction with most benzodiazepines. 

Whole-body autoradiography of mice was employed as the technique to study the distribution of diazepam, chlordiazepoxide, and their metabolites. The former con und was more highly localized in body fat thetn the latter however, the rate of penetration of chlordiazepoxide into the brain was slower than that of diazepam. The major metabolite of diazepam was the N-demethylated compound. vitro, in preparations of rat or mouse liver microsomes, the major metabolites of diazepam were N-methyloxazepam or N-demethyldiazepam, respectively. Diazepam inhibited the conversion by mouse liver microsomes of N-methyloxazepam to oxazepam. Prazepam, the cyclopropyl derivative of the N-methyl group of diazepam, was metabolized by the dog in a manner similar to that for dicusepam the major urinairy metabolite was oxazepam glucuronide. ... 

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. 

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. 

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. 

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). 

In a patient lacking liver function, benzodiazepines that are metabolized via extrahepatic conjugation (e.g., lorazepam, oxazepam) are safer in terms of the possibility of excessive CNS depression. Lorazepam is metabolized, probably in the lungs, via glucuronidation. Although benzodiazepine actions can be reversed, the drug that acts as an antagonist is flumazenil, not naloxone. 

These inhibit oxidative metabolism and at the same time enhance glucuronidation. Consequently, the half-lives of benzodiazepines such as alprazolam, chlordiazepoxide, diazepam, and triazolam were found to be increased, and the half-life of Iorazepam, and to a lesser extent that of oxazepam, can be significantly reduced. 

Chlordiazepoxide is well absorbed after oral administration, and peak blood concentration usually is reached in approximately 4 hours. Intramuscular absorption of chlordiazepoxide, however, is slower and erratic. The half-life of chlordiazepoxide Is variable but usually quite long (6-30 hours). The initial N-demethylation product, N-desmethylchloridiazepoxide, undergoes deamination to form the demoxepam (Fig. 22.18), which is extensively metabolized, and less than 1 % of a dose of chlordiazepoxide is excreted as demoxepam. Demoxepam can undergo four different metabolic fates. Removal of the N-oxide moiety yields the active metabolite, N-desmethyIdiazepam (desoxydemoxepam). This product is a metabolite of both chlordiazepoxide and diazepam and can be hydroxylated to yield oxazepam, another active metabolite that is rapidly glucuronidated... 

The second group includes those that are metabolized only by conjugation to water-soluble glucuronides (subsequently excreted in the urine), which are pharmacologically inactive (e.g., lorazepam and oxazepam). 

Disulfiram inhibits the initial metabolism (A-demethylation and oxidation) of both chlordiazepoxide and diazepam by the liver so that an alternative but slower metabolic pathway is used. This results in the accumulation of these benzodiazepines in the body. In contrast, the metabolism (glucuronidation) of oxazepam and lorazepam is minimally affected by disulfiram so that their clearance from the body remains largely unaffected. The possible interaction between disulfiram and temazepam is not understood, as temazepam is also mainly eliminated in the urine as the inactive glucuronide metabolite, and so its metabolism would not be expected to be affected by disulfiram. 

Lorazepam, oxazepam and temazepam are metabolised by a different metabolic pathway involving glucuronidation, which is not affected by cimetidine, and so they do not usually interact. 

What is known suggests that isoniazid acts as an enzyme inhibitor, decreasing the metabolism and loss of diazepam and triazolam from the body, thereby increasing and prolonging their effects. Oxazepam which is metabolised by glucuronidation would be unlikely to interact. 

Benzodiazepines and their metabolites are normally excreted as the glucuronide conjngates and require either acid or enzyme hydrolysis for good recovery. Hydrolysis of the benzodiazepines yields the corresponding benzophenone, which can be identified by GCMS and related back to the parent benzodiazepine. In some cases, however, the specific benzodiazepine cannot be identified because some benzodiazepines yield the same benzophenone after acid hydrolysis. In addition, some benzodiazepines yield the same metabolites. For example, diazepam and chlordiazepoxide both metabolize to desmethyldiazepam and oxazepam. To eliminate this problem and lower the limit of detection, it is possible to derivatize the benzodiazepines using BSTFA to form their trimethylsilyl derivatives. 

Metabolism of prazepam (51a) by human and animal liver preparations gave mainly desalkylprazepam (31b) plus a small amount of oxazepam, but no 3 hyurinary metabolites of prazepam In roan were glucuronides of 31c and oxazepam and small amounts of 31b,... 

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