Diazepam metabolism/excretion

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. 

Benzodiazepines are lipid soluble and are found in breast milk. They are metabolized in the liver and excreted as glucuro-nide metabolites at different rates. For example, the half-life of triazolam is 2 to 5 hours, while that of diazepam varies between... 

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. 

The principal objective of drug metabolism is to make a drug available for excretion by urine or bile. The renal and biliary systems can excrete water-soluble molecules, whereas water-insoluble drugs must first be converted to a soluble form before they can be excreted. Drug metabolism, therefore, is principally, but not exclusively, of importance for drugs that are non-polar. Metabolism usually results in inactivation of the drug but there are exceptions, e.g. diazepam is metabolised to an active metabolite desmethyidiazepam, which has a much longer duration of action than the parent compound. 

Most muscle relaxants are absorbed fairly easily from the gastrointestinal tract, and the oral route is the most frequent method of drug administration. In cases of severe spasms, certain drugs such as methocarbamol and orphenadrine can be injected intramuscularly or intravenously to permit a more rapid effect. Likewise, diazepam and dantrolene can be injected to treat spasticity if the situation warrants a faster onset. As discussed earlier, continuous intrathecal baclofen administration may be used in certain patients with severe spasticity, and local injection of botulinum toxin is a possible strategy for treating focal dystonias and spasticity. Metabolism of muscle relaxants is usually accomplished by hepatic microsomal enzymes and the metabolite or intact drug is excreted through the kidneys. 

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. 

Treatment of the adverse effects of PCP is difficult for several reasons. PCP has a very high volume of distribution (6.2 liters per kilogram (L/kg) in humans) and its clearance is primarily by metabolism (Cook et al. 1982) with only a small contribution from renal excretion. Its major sites of action in the central nervous system (CNS) are far removed from the beneficial effects of most traditional treatment methods such as dialysis. In addition, there is no specific antagonist for PCP s adverse effects. These pharmacokinetic and receptor-medicated characteristics make it very difficult to develop effective treatment strategies. Some of the current methods for treatment of overdose are urine acidification, diazepam administration to control convulsions (Aronow and Done 1978 ... 

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. 

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... 

I. Pharmacology. Phenobarbital Is a barbiturate commonly used as an anticonvulsant. Because of the delay In onset of the therapeutic effect of phenobarbital, diazepam (see p 415) Is usually the Initial agent for parenteral anticonvulsant therapy. After an oral dose of phenobarbital, peak brain concentrations are achieved within 10-15 hours. Onset of effect after intravenous administration is usually within 5 minutes, although peak effects may take up to 30 minutes. Therapeutic plasma levels are 15-35 mg/L. The dmg is eliminated by metabolism and renal excretion, and the elimination half-life is 48-100 hours. 

Psychoactive benzodiazepines - The metabolism of prazepam, the cyclopropyl derivative of the N-methyl group of diazepam, was studied in man. This compound is slowly absorbed and slowly excreted, primarily as conjugates. Dealkylated prazepam was the only unconjugated metabolite found in urine, whereas 3-hydroxyprazepam and oxazepam were excreted as conjugates. At least 10 other i tabolites were present, but not identified. The principal metabolic reaction for prazepam, but not for diazepam, was 3-hydroxylation. It is suggested that the cyclopropylmethylene group is more insistent to oxidative dealkylation than is a methyl group in the same position. 

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. 

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