Clorazepate pharmacokinetics

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Following a single oral dose of 15 mg to 4 subjects, peak blood concentrations of desmethyldiazepam of 0.14 to 0.18 pg/ml (mean 0.16) were attained in 0.5 to 1 hour peak blood-clorazepate concentrations of 0.03 to 0.11 pg/ml (mean 0.06) were reported at about 1 hour (C. W. Abruzzoe al., J. Pharmacokinet. Biopharm., 1977, 5, 377-390). 

Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compoimds produce active metabolites, some with long t) which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t/ 80 h). 

Some studies have suggested that smoking does not affect the pharmacokinetics of diazepam, chlordiazepoxide, clorazepate, lorazepam, ... 

Norman TR, Fulton A, Burrows GD, Maguire KP. Pharmacokinetics of N-desmethyldi-azepam after a single oral dose of clorazepate the effect of smoking. EurJ Clin Pharmacol (1981)21,229-33,... 

Several of the most-used benzodiazepine tranquillizers seem to act as the metabolic product, nordazepam (3.47), which has the full therapeutic action of the starting materials, and acts faster. Thus diazepam (12.95) ( Valium ) loses 1-Me, chlordiazepoxide ( Librium ) loses 4-0 and hydrolyses 2-MeNH- to=0, whereas clorazepate ( Tranxene ) loses 4-CO2, and in each case nordazepam is the product. While the latter is available for prescribing, clinical experience with the pro-drugs is greater moreover they have very different pharmacokinetics, diazepam being absorbed quickly and chlordiazepoxide slowly from the gastrointestinal tract. See further Section 12.7 Garattini, Mussini and Randall (1973), Nicholson a/. (1976), and Hollister (1978). 

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