Absorption clorazepate

Clorazepate is a prodrug and possesses no anxiolytic effects until metabolism to DMDZ. Before absorption, clorazepate is metabolized rapidly in the stomach through a pH-dependent process under acidic conditions. 

Diarrheal conditions may decrease drug absorption as a result of reduced intestinal residence time. The absorption of several drugs was decreased in response to lactose- and saline-induced diarrhea [145]. Digoxin absorption from tablets was impaired in one subject who developed chronic diarrhea as a result of x-ray treatment [146]. Abdominal radiation or the underlying disease has been shown to reduce digoxin and clorazepate absorption [147]. A dosage form that provides rapid drug dissolution (e.g., solution) may partially resolve this problem. 

BZDs with rapid absorption produce a more rapid onset of clinical activity than those with slower absorption. BZDs given orally differ in their speed of absorption from the gastrointestinal tract. For example, absorption time is 0.5 hours for clorazepate, 1 hours for diazepam, 1.3 hours for triazolam, 2 hours for alprazolam and lorazepam, 2 to 3 hours for oxazepam, and 3.6 hours for flurazepam. Absorption, however, may be influenced by the presence or absence of food in the gastrointestinal tract. Thus, patients who take a BZD hypnotic with a bedtime snack may experience a slower onset of hypnotic activity than if the same drug were taken several hours after a meal. 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

A few cases have been reported of slight and insignificant delays in the absorption of benzodiazepines (chlordiazepoxide and diazepam) and possibly more significant delays in absorption with clorazepate (activated by acid conditions). 

Although antacids can moderately change the rate of absorption of chlordiazepoxide, clorazepate and diazepam, no adverse interaction of clinical importance has been reported. 

The delay in the absorption of ehlordiazepoxide and diazepam is attributed to the effeet of the antaeid on gastrie emptying. Clorazepate on the other hand is a prodrug, whieh needs aeid eonditions in the stomach for conversion by hydrolysis and deearboxylation to its aetive form. Antacids are presumed to inhibit this eonversion by raising the pH of the stomach contents. ... 

Chun AHC, Carrigan PJ, Hoffman DJ, Kershner RP, Stuart JD. Effect of antacids on absorption of clorazepate. Clin Pharmacol Ther (1977) 22, 329-35. 

Shader RI, Georgotas A, Greenblatt DJ, Harmatz JS, Allen MD. Impaired absorption of des-melhyldiazepam from clorazepate by magnesium aluminum hydroxide. Clin Pharmacol Ther (1978)24, 308-15. 

Abruzzo CW, Macasieb T, Weinfeld R, Rider JA, Kaplan SA. Changes in die oral absorption characteristics in man of dipotassium clorazepate at normal and elevated gastric pH. J Phar-macoldnetBiopharm (1977) 5, 377-90. 

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