Diazepam clearance

Because diazepam clearance is decreased in the elderly and in patients with hepatic insufficiency, a dosage reduction may be warranted. Intravenous diazepam should be used cautiously in patients who are elderly, very III, or have limited pulmonary reserve, because respiratory depression has occurred. Rarely, IV diazepam is given to patients for absence status (typical and atypical), because It will precipitate tonic status epileptic. 

One study in 8 healthy subjects found that omeprazole 40 mg daily for one week reduced the clearance of a single 100-microgram/kg intravenous dose of diazepam by 54%, while another study found that omeprazole 20 mg reduced diazepam clearance by 27%. ... 

A further study found that omeprazole 40 mg reduced the oral clearance of diazepam by 42% in white American subjects but only by 21% in Chinese subjects. Metaboliser status (see Genetic factors , (p.4)) was also found to be important in another study of this interaction only extensive metabolisers of CYP2C19 showed a significant decrease in diazepam clearance when given omeprazole. ... 

Fig. 2. The relationship between age and the elimination half-life (upper panel), volume of distribution (middle panel) and plasma clearance (lower panel) of diazepam in healthy volunteers. From Klotz et al., 1975 used with permission.

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

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. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

Carlile DJ, Zomorodi K, Houston JB. 1997. Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver studies with induced livers involving diazepam. Drug Metab Dispos 25 903-911. 

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). 

In a double blind, placebo-controlled, crossover study in eight white and seven Chinese men who were extensive metabolizers of debrisoquine and mephenytoin, omeprazole 40 mg/day reduced the oral clearance of diazepam by 38% and increased desmethyldiazepam AUC by 42%. In contrast, in the Chinese men the oral clearance of diazepam fell by only 21% and desmethyldiazepam AUC by 25%. The authors concluded that the extent of the inhibitory effect of omeprazole on diazepam metabolism depends on ethnicity (51). Differences between Caucasians and Asians may account for such effects. 

Cimetidine may reduce the clearance and raise the levels of diazepam... 

May reduce fhe clearance of diazepam or frazodone, fhus increasing fheir levels... 

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