Oxazepam pharmacokinetics

Scott AK, Khir ASM, Steele WH, Hawksworth GM, Petrie JC Oxazepam pharmacokinetics in patients with epilepty treated long-term with phenytoin alone or in combinatic i with phe-nobarbitcxie. BrJ Clin Pharmacol (1983) 16,441-4. 

After taking disulfiram 500 mg daily for 14 to 16 days, the plasma clearance of single doses of chlordiazepoxide and diazepam were reduced by 54% and 41%, respectively, and Ihe half-lives were increased by 84% and 37%, respectively. The plasma levels of chlordiazepoxide were approximately doubled. Oxazepam was also given following disulfiram treat-menl bul changes in oxazepam pharmacokinetics were minimal. There was no difference in Ihe interaction belween alcoholic subjects (without hepatic cirrhosis) and healthy subjects. ... 

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. 

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.)... 

Sonne J, Loft S, Dossing M et al. (1991) Single dose pharmacokinetics and pharmacodynamics of oral oxazepam in very elderly institutionalised subjects. Br J Chn Pharmacol 31(6) 719-722 Taylor S, McCracken CF, Wilson KC et al. (1998) Extent and appropriateness of benzodiazepine use. Results from an elderly urban community. Br J Psychiatry 173 433—438... 

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. 

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. 

Knowing the differential pharmacokinetics for a class of drugs allows the clinician to choose specific members to either achieve a faster onset or a delayed offset of action (13, 14, 17, 18). For example, lorazepam is rapidly absorbed from the gastrointestinal tract into the systemic circulation and from there distributed into the brain. In contrast, oxazepam, the most polar BZD, is slowly absorbed from the gastrointestinal tract. Even after oxazepam is in the systemic circulation, it slowly enters tissue compartments, including the brain, during the distribution phase. Unlike lorazepam, oxazepam is not available in either the intramuscular or intravenous formulations. Thus, lorazepam would be preferable to achieve acute control of alcohol withdrawal (e.g., delirium tremens), whereas oxazepam would better stabilize a dependency-prone patient on sedative-hypnotics, because it does not cause the euphoria seen with the more rapidly absorbed members of this class. 

Oxazepam, others Positive modulators of the receptors, increase frequency of channel opening Enhances GABAergic synaptic transmission attenuates withdrawal symptoms (tremor, hallucinations, anxiety) in alcoholics prevents withdrawal seizures Delirium tremens Half-life 4-15 h pharmacokinetics not affected by decreased liver function... 

The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relationship to the time course of pharmacologic effects. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22-1. 

Note. For a review of the clinical pharmacokinetics of oxazepam see D. J. Greenblatt, Clin. Pharmacokinet., 1981, d, 89-105. 

Greenbiatt DJ. Ciinicai pharmacokinetics of oxazepam and iorazepam. Ciin Pharmacokinet f98f 6 89-f05. 

Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 1981 6 89-105. 

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). 

In healthy volunteers, the half-Ufe of triazolam was prolonged from 2.5 to 3.3 hours when it was given with isoniazid (SEDA-9, 267). However, isoniazid did not affect the pharmacokinetics of oxazepam. 

Mole L, Israelski D, Bubp J, O Hanley P, Merigan T, Blaschke T. Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient. J Acquir Immune Defic Syndr 1993 6(l) 56-60. 

Table 1-2 includes a list of major CYPs that are responsible for the phase I metabolism of commonly used psychotropics as well as selected substances that are psychoactive and are commonly used by psychiatric patients. With very few exceptions (e.g., lithium does not require biotransformation lorazepam and oxazepam are directly conjugated without first going through oxidation), the pharmacokinetics of practically all psychotropics are dependent on one or more of the CYPs, whose activity significantly influences the tissue concentrations, dose requirement, and side-effect profiles of their substrates. 

Vree, T.B. Baars, A.M. Wuis, E.W. Direct high pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glu-curonide conjugates. Pharm.WeekblJSci]., 1991, 13, 83—90... 

Benzodiazepines Paroxetine has not been found to alter the pharmacokinetics of diazepam or oxazepam. From a pharmacokinetic perspective, the combined use of paroxetine and benzodiazepines is considered relatively safe. 

This increases the free fraction of cbiordiazepoxide, diazepam, iorazepam, and oxazepam. The mechanism is probably via induction by beparin of concomitant free fatty acid changes, which consequently alter benzodiazepine pharmacokinetics. 

Active metabolites may have superior pharmacological, pharmacokinetic, and safety profiles compared to their respective parent molecules (Fura, 2006 Fura et al., 2004). As a result, a number of active metabolites have been developed and marketed as drugs with improved profiles relative to their parent molecules. Examples of active metabolites of marketed drugs that have been developed as drugs include acetaminophen, oxyphenbutazone, oxazepam, cetirizine (Zyrtec), fexofenadine (Allegra), and desloratadine (Clarinex). Each of these drugs provides a spedlic benefit over the parent molecule and is superior in one or more of the categories described above. 

Klotz U, Reimann I Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam Eur J Clin Pharmacol 9W) 18, 517-20... 

A study in 9 healthy subjects found that isoniazid 90 mg twice daily for 3 days had no effect on the pharmacokinetics of a single 30-mg oral dose of oxazepam. Similarly, in another study, the pharmacokinetics of clo-tiazepam were not altered by isoniazid. ... 

No important changes in the pharmacokinetics of paroxetine were seen when 12 healthy subjects given paroxetine 30 mg daily were also given diazepam 5 mg three times a day. Adverse events were not inereased by the combination. In another study it was foimd that paroxetine did not increase the impairment of a number of psychomotor tests eaused by oxazepam.In vitro studies using human liver mierosomal enzymes have shown that paroxetine is a relatively weak inhibitor of alprazolam metabolism mediated by the cytochrome P450 subfamily CYP3A. Furthermore, a randomised, placebo-controlled study in 22 healthy subjeets reported no evidence for a pharmacokinetic or pharmacological interaction between paroxetine and alprazolam. ... 

A study in healthy subjects given tianeptine 12.5 mg and oxazepam 10 mg both three times daily found no significant changes in the pharmacokinetics of either drug. ... 

Toon S, HoltBL, Langley SJ, Mullins FGP, Rowland M, Halliday MS, Salvadori C, Delalleau B. Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state. Psychopharmacology (Berl) (1990) 101, 226-32. 

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