Demethyl diazepam

N-Demethyl-diazepam, a metabolite of diazepam 13.77) has a quicker onset and more prolonged hypnotic action than diazepam, and may be responsible for the latter s therapeutic benefits (Nicholson et al., 1976). 

In addition, other drugs such as alosetron (2), cyproheptadine (12), diazepam (13) or tamoxifen (49) are AT-demethylated by various microorganisms as a major metabolic route. The carboxylic acid resulting from the oxidative cleavage of the piperidine ring of phencyclidine (36), probably proceeding through an... 

Diazepam, oxazepam, and N-desmethyldiazepam have been determined under isocratic conditions (342) a somewhat more sensitive assay for diazepam and N-methyldiazepam has been reported (545). The closely related compounds, chlordiazepoxide and its N-demethyl metabolite, have also been determined (344). Analysis of the antidepressant amitriptyline, its metabolites and related drugs have been carried out using a four-component solvent (345, 346) and also aqueous acetonitrile (547). 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

Those biotransformed by oxidative metabolism in the liver, primarily Ai-demethylation or hydroxylation (e.g., adinazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, and medazepam), often yield pharmacologically active metabolites that must undergo further metabolic steps before excretion. 

A2 Tertiary amine TCAs, duloxetine, theophylline, phenacetin, TCAs (demethylation), clozapine, diazepam, caffeine Fluvoxamine, fluoxetine, moclobemide, ramelteon Tobacco, omeprazole... 

Disposition in the Body. Readily absorbed after oral administration. Rapidly metabolised by A-demethylation to desmethyl-ketazolam and desmethyldiazepam (nordazepam). About 80% of a dose is excreted in the urine as metabolites with only traces of unchanged drug. Of the material excreted in the urine, about 56% is oxazepam and the remainder is a mixture of minor metabolites including diazepam, desmethyldiazepam, temazepam, and other unidentified metabolites. About 20% of a dose is eliminated in the faeces, mainly as metabolites. 

Following a single oral dose of 30 mg of C-labelled ketazolam, peak plasma concentrations of about 0.004 pg/ml of ketazolam, 0.017 pg/ml of diazepam, and 0.127 ig/ml of A -demethylated metabolites were attained in 2, 10, and 14 hours respectively (F. S. Ebertsjun. etal.. Pharmacologist, 1977,19,165). 

Yasumori, T. Nagata, K. Yang, S. K. Chen, L.-S. Murayama, N. Yamazoe, Y Kato, R. Cytochrome P450 mediated metabolism of diazepam in human and rat involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner, Pharmacogenetics 199i, 3,291-301. 

O-glucuronide, diazepam (which is N-demethylated to nordiazepam), and codeine (which is O-demethylated to morphine). 

N-Demethylation is a newly described metabolic transformation of chlordiazepoxide in man, the rat and the dog. The effect of dose differences on the observed concentrations of diazepam and its metabolites in the blood and tissues of man has been studied.91 Repeated 30-mg. doses cause a progressiye rise. The principal (demethylated) metabolite appears after 24 hours, rises until its concentration is comparable to diazepam and persists longer than diazepam after dosing ends. Higher chronically administered doses result in a ratio of metabolite to drug of 2.5 to 1.0. Only traces of 1-methyloxazepam and oxazepam are observed in blood. 

Studies by Klotz et al. (1975,1976a,b) suggest that biliary excretion of diazepam is unimportant in man, but there is some evidence (see above) for species differences (Klotz etal., 1975,1976a van der Kleijn et al., 1971). Urinary excretion of diazepam is mainly in the form of sulphate and glu-curonide conjugates (Mandelli et al., 1978). The main metabolic pathway is demethylation and hydroxylation to metabolites with CNS depressant activity in animals and man. These metabolites are desmethyldiazepam and oxazepam. 

Recombinant human CYP2D6 was shown to be selective for the O-demethyla-tion of dextromethorphan at or near the K n for this cytochrome s interaction with this substrate (at a concentration of 3 pM), whereas at higher substrate concentrations CYPs of the cytochrome 2C family contributed significantly to the metabolism of the drug. Similarly, diazepam at a concentration of 100 pM was N-demethylated principally by CYPs 3A4 and 2C19. However, at the lower concentration of 20 pM, the metabolism mediated by CYP3A4 was reduced to 30% that of CYP2C19. 

Isotretinoin Diclofenac (4 -hydroxylation) Suprofen Diazepam (N-demethylation)... 

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... 

Metabolism of omeprazole and other proton pump inhibitors occurs primarily in the liver (Fig. 37.19). The sulfone, hydroxylated, and O-demethylated metabolites have been reported as products. Omeprazole is a substrate primarily for CYP2C19 and may elevate concentrations of other substrates for this enzyme (e g., diazepam) when given concurrently. The CYP3A4 contributes to a lesser extent. Further oxidation of the sulfone affords additional metabolites. 

Another study in healthy subjects found that dextropropoxyphene 65 mg every 6 hours prolonged the alprazolam half-life from 11.6 to 18.3 hours, and decreased the clearance from 1.3 to 0.8 mL/minute per kg. The pharmacokinetics of single doses of diazepam and lorazepam were not significantly affected. It would seem that dextropropoxyphene inhibits the metabolism (hydroxylation) of the alprazolam by the liver, thereby reducing its loss from the body, but has little or no effect on the A/-demethylation or glucuronidation of the other two benzodiazepines. The clinical importance of this is uncertain, but the inference to be drawn is that the CNS depressant effects of alprazolam will be increased, over and above the simple additive CNS depressant effects likely when other benzodiazepines and dextropropoxyphene are taken together. More study is needed. 

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. 

Diazepam is primarily metabolized by hepatic cytochrome enzyme responsible for S-mephenytoin hydrox-ylation, with very little unchanged drug eliminated in the urine [1,2]. Hepatic N-demethylation results in the formation of the active metahohte desmethyldiazepam. This metabolite is hydroxylated to form oxazepam. Another minor active metabohte is temazepam. The half-life ty )of diazepam ranges from approximately 24 hours to more than 48 hours. With chronic dosing, steady-state concentrations of diazepam are achieved between 5 days and 2 weeks. The half-life is prolonged in the elderly and in patients with cirrhosis or hepatitis. 

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. ... 

Anti-anxiety drugs. The most used of the anxiolytics are the benzodiazepines which not only relieve anxiety, and relax skeletal muscle, but can suppress convulsions, all accomplished apparently by augmenting the inhibitory transmission effected by gamma-aminobutyric acid in the spinal cord (Choi, Farb, and Fischbach, 1977). Discovered in 1933, the benzodiazepines gained clinical acceptance about 1965 (Zbinden and Randall, 1967). The first used member was chlordiazepoxide ( Librium ) followed by the simpler, but more potent, diazepam (/J.//) ( Valium ). Some think that diazepam is a pro-drug for oxazepam ( Serax ) which is a N-demethylated and 3-hydroxylated metabolic product, and is frequently prescribed as such. Related benzodiazepines such as nitrazepam ( Mogadon ) and flurazepam are much used as hypnotics in the place of barbiturates. 

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