Diazepam pharmacokinetics

Kumana CR, Lauder IJ, Chan M, Ko W, Lin HF (1987) Differences in diazepam pharmacokinetics in Chinese and white Caucasians—relation to body lipid stores. Eur J Clin Pharmacol 32 211-215... 

Sohn DR, Kusaka M, Ishizaki T, et al. Incidence of S-mephenytom hydroxylation deficiency in a Korean population and the inter-phenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992 52 160-169. 

Inomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther 2005 78 647-55. 

Capacio, B.R., Whalley, C.E., Byers, C.E. and McDonough, J.H. 2001. Intramuscular diazepam pharmacokinetics in soman-exposed guinea pigs. J. Appl. Toxicol., 21 Suppl LS67-S74. 

Several studies have reported that alcohol increases plasma levels of diazepam and that alcohol accelerates the absorption of diazepam, but others have suggested that alcohol has no significant effect on diazepam pharmacokinetics. Plasma levels of brotizolam and clobazam may be increased by alcohol. One study reported that the plasma levels of triazolam were increased by alcohol, but other studies have found only a minimal pharmacokinetic interaction. However, an in vitro study demonstrated that alcohol inhibited the metabolism of triazolam by the cytochrome P450 isoenzyme CYP3A. Another in vitro study reported that the formation of flunitrazepam metabolites was weakly inhibited by alcohol, but a pharmacokinetic study suggested that there was no interaction. Alcohol appears to have minimal effects on the pharmacokinetics of alprazolam, and zopiclone. ... 

Dressier R, Carter D, Winters L. Enprostil, in contrast to cimetidine, does not affect diazepam pharmacokinetics. Adv Therapy (1988) 5,306-12. 

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. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Y Igari, Y Sugiyama, Y Sawada, T Iga, M Hanano. Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model. J Pharmacokin Biopharm 11 577-593, 1983. 

For plasma and blood experiments, LC effluent was directed to waste for the first 1 min. Conventional blood analysis by drawing 1 mL samples from the saphenous catheter was used to validate SPME results. These samples were subjected to PPT with acetonitrile and the supernatant from centrifugation was analyzed. The SPME probes were also evaluated for pharmacokinetic analysis of diazepam and its metabolites, oxazepam and nordiazepam. Good correlation was obtained for conventional blood drawn from saphenous and cephalic sites of the animals, as shown in Figure 1.48. Although the analytical parameters for the automated study need improvement, the authors cite the study as a first demonstration of SPME technology for in vivo analysis. 

FIGURE 1.48 (A) Averaged diazepam profiles from pharmacokinetic studies. (B) Diazepam profile for one study with one dog, both catheters cephalic. (C) Averaged nordiazepam profiles from pharmacokinetic studies. (D) Averaged oxazepam profiles from pharmacokinetic studies.168 (Reproduced with permission from the American Chemical Society and the authors.)... 

Benzodiazepines have similar pharmacological properties and are used in anxiety and insomnia. The choice of which benzodiazepine to use usually lies with the pharmacodynamic and pharmacokinetic properties, which vary across the class. For example, diazepam, flurazepam and nitrazepam have a prolonged duration of action whereas lorazepam and temazepam have a shorter duration of action. 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

The pharmacokinetic profile is different with different compounds. Diazepam after oral administration is completely and rapidly absorbed from the proximal small intestine. Oxazepam is least rapidly absorbed while lorazepam is an intermediately absorbed between these two. They are metabolised in liver by dealkylation and hydroxylation and excreted in urine as glu-curonide conjugates. They cross the placental barrier and are secreted in milk. 

Greenblatt DJ, Ehrenberg BL, Gunderman JS, et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam and placebo. Clin Pharmacol Ther 1989 45(4) 356-365. 

Ishihara K, Kashida H, Yuzurihara M, et al. Interaction of drugs and Chinese herbs pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica. J Pharm Pharmacol 2000 52 1023-1029. 

Ozdemir M, et al. Interaction between grapefruit juiee and diazepam in humans. Eur J Drug Metab Pharmacokinet 1998 23(l) 55-59. 

Saano, V., Hansen, P.P., and Paronen, P., Interactions and comparative effects of zoplicone, diazepam and lorazepam on psychomotor performance and on elimination pharmacokinetics in healthy volunteers, Pharmacol. Toxicol., 70, 135, 1992. 

Freidman, H. et al., Pharmacokinetics and pharmacodynamics of oral diazepam effect of dose, plasma concentration, and time, Clin. Pharmacol. Ther., 52, 139, 1992. 

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. 

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