Chlordiazepoxide metabolism

Taylor, KM and Laverty, R (1969) The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur. J. Pharmacol. 8 296-301. 

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. 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

The BZs are all metabolized in the liver via the hepatic cytochrome P450 (CYP) enzymes through one or both of the following pathways phase I oxidation and dealkylation, and/or phase II conjugation to glucuron-ides, sulfates, and acetylated compounds. Diazepam, chlordiazepoxide, and flurazepam all undergo both phase 1 and phase 11 metabolism. Lorazepam, lorme-tazepam, oxazepam, and temazepam are all metabolized by phase 11 alone and are better tolerated by patients with liver impairment. 

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. 

Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longer-acting benzodiazepine such as chlordiazepoxide is preferred. 

Benzodiazepines [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. 

Benzodiazepines undergo extensive and complex metabolism. They are excreted mainly in the urine, largely in the form of several metabolites. Biotransformation processes include mainly hydroxylation and A-dealkylation reactions, whereas the end-products include both free and conjugated compounds (116). Chlordiazepoxide, for example, is metabolized to oxazepam and other metabolites and, depending on its dosage, urine may contain significant concentrations of oxazepam (117). 

Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (chlordiazepoxide, alprazolam, diazepam) or nitroreduction (nitrazepam) (334). Oral contraceptives inhibit enzyme activity and reduce the clearances of these drugs. There is nevertheless no evidence that these interactions are of clinical importance. For other benzodiazepines that undergo oxidative metabolism, such as bromazepam and clotiazepam, no change has ever been found in oral contraceptive users. 

Fate Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic microsomal metabolizing system (see p. 14) to compounds that are also active. For these benzodiazepines, the apparent half-life of the drug represents the combined actions of the parent drug and its metabolites. The benzodiazepines are excreted in urine as glucuronides or oxidized metabolites. 

Disulfiram inhibits hepatic drug metabolism and can prolong the effects of substances that are normally metabolized in the liver. This has been studied for various benzodiazepines. The clearances of chlordiazepoxide and diazepam were significantly reduced and their half-lives prolonged by disulfiram (43). 

The major pathway for chlordiazepoxide metabolism involves hydrolysis of the 2-methylamino substituent to yield the lactam derivative, demoxepam. This is excreted in the urine unchanged or undergoes further cleavage to the corresponding acid before excretion... 

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