Alprazolam pharmacokinetics

Scavone JM, Greenblatt DJ, Locniskar A, et al Alprazolam pharmacokinetics in women on low-dose oral contraceptives. J Clin Pharmacol 28 454-457, 1988 Schatzberg AF, Ballenger JC Decisions for the clinician in the treatment of panic disorder when to treat, which treatment to use, and how long to treat. J Clin Psychiatry 52 [suppl) 26-31, 1991... 

Gashaw I, Kirchheiner J, Goldammer M, Bauer S, Seidemann J, Zoller K, Mrozikiewicz PM, Roots I, Brockmoller J. Cytochrome p450 3A4 messenger ribonucleic acid induction by rifampicin in human peripheral blood mononuclear cells correlation with alprazolam pharmacokinetics. Clin Pharmacol Ther 2003 74 448-457. 

The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (98). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32% citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not. 

Greenblatt DJ, vonMolticeLL, Harmatz JS, CirauloDA, Shader RI. Alprazolam pharmacokinetics, metabolism, and plasma levels clinical implications. J Clin Psychiatry ( 1993) 54, 10 (Siq)pl),4-ll. 

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. 

Ciraulo DA, Nace EP Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Greenblatt DJ, et al Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men. J Clin Psychiatry 49 333—337, 1988a... 

Yuan R, Flockhart DA, Balian JD Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999,39 1109-1125. 

Benzodiazepines. The introduction of the benzodiazepines represented a significant advance in the treatment of panic disorder. In contrast to MAOIs and TCAs, the benzodiazepines begin to provide relief the very first day of treatment, and many patients experience a complete response by the end of the second week of therapy. All benzodiazepines should theoretically alleviate the symptoms of a panic attack at comparable doses, but the benzodiazepines of choice are alprazolam (Xanax, Xanax XR) and clonazepam (Klonopin). It likely is not coincidental that these two are among the highest potency benzodiazepines. However, they differ considerably from a pharmacokinetic standpoint. If clonazepam is the tortoise of benzodiazepines, then alprazolam is the hare. 

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. 

DeVane, C.L., Ware, M.R., and Lydiard, R.B. (1991) Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines alprazolam, adinazolam, and clonazepam. Psychophar-macol Bull 27 463-473. 

Oo, C.Y., Kuhn, R.J., Desai, N., Wright, C.E., and McNamara, P.J. (1995) Pharmacokinetics in lactating women prediction of alprazolam transfer into milk. Br J Clin Pharmacol 40 231-236. 

Csernansky JG, Lombrozo L, Gulevich GD, et al. Treatment of negative schizophrenic symptoms with alprazolam a preliminary open-label study. J Clin Psychopharmacol 1984 4 349-352. Douyon R, Angrist B, Peselow E, et al. Neuroleptic augmentation with alprazolam clinical effects and pharmacokinetic correlates. Am J Psychiatry 1989 146 231-234. 

A BZD s pharmacokinetics may play a role in the occurrence, in part accounting for the increase in its incidence after the advent of short-acting BZD anxiolytics and hypnotics (e.g., lorazepam, alprazolam, and triazolam). 

Ballenger JC, Lydiard RB, Lesser IM, et al. Acute fixed dose alprazolam study in panic disorder patients. Presented at the Pharmacology/Pharmacokinetic Studies Workshop at the Panic Disorder Biological Research Workshop, Washington, DC, April 1986. 

Alprazolam did not exhibit any changes in pharmacokinetic parameters when administered concomitantly with GFJ (130) in a single dose experiment. When predosing existed, GFJ increased the exposure of alprazolam only in smokers. However, this interaction seems unlikely to be clinically relevant. In both parts of this study psychomotor fimction remained unchanged however, there was a small decrease in cognitive speed in the single dose part at one and two hours after dosing. Midazolam (6,15,133,134) and triazolam... 

Yasui N, Kondo T, Furukori H, et al. Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology (Berl) 2000 150(2) 185-190. 

Hall J, Naranjo CA, Sproule BA, et al. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 2003 23 349-357. 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam therapeutic implications. Clin Pharmacokinet 1993 24 453-471. 

Lau CE, Wang Y, Falk JL. 1997. Differential reinforcement of low rate performance, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling independent interaction of alprazolam and caffeine. J Pharmacol Exp Ther 281 1013-1029. 

SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 out-patients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (97). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. 

The effects of venlafaxine on the pharmacokinetics of alprazolam have been investigated in 16 healthy volunteers. Steady-state venlafaxine 75 mg bd did not inhibit CYP3A4 metabolism of a single dose of alprazolam 2 mg (33). 

Klockowski PM. Effect of venlafaxine on the pharmacokinetics of alprazolam. Psychopharmacol Bull 1998 34(2) 211-9. 

Lasher TA, Fleishaker JC, Steenwyk RC, Antal EJ. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology (Berl) 1991 104(3) 323-7. 

In an open, randomized, crossover study in 12 healthy men and women, alosetron 1 mg bd did not affect the pharmacokinetics of a single oral dose of alprazolam 1 mg (35). 

There have been two studies of the effects of repeated ingestion of grapefruit juice on the pharmacokinetics and pharmacodynamics of both single and multiple oral doses of alprazolam in a total of 19 subjects (38). Grapefruit juice altered neither the steady-state plasma concentration of alprazolam nor its clinical effects. 

In a double-blind, crossover, pharmacokinetic and pharmacodynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam (39). 

A within-subject, double-bhnd, placebo-controlled, parallel design has been used to measure the effects of citalo-pram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) (45). Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential effects of citalopram and fluoxetine on alprazolam kinetics. 

D Souza DL, Levasseur LM, Nezamis J, Robbins DK, Simms L, Koch KM. Effect of alosetron on the pharmacokinetics of alprazolam. J Clin Pharmacol 2001 41(4) 452-4. 

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