Plasma Concentrations Of Alprazolam Research Articles

Absence of Food Effect on the Extent of Alprazolam Absorption from an Orally Disintegrating Tablet

To evaluate the effect of a standardized meal on the bioavailability of alprazolam formulated as an immediate-release orally disintegrating tablet (ODT) in healthy volunteers. Single-dose, randomized, open-label, two-period crossover study. Contract research organization clinic. Sixteen healthy volunteers (seven men, nine women), aged 20-50 years. Intervention. Subjects were administered a single dose of alprazolam ODT 1.0 mg during two treatment periods-under fasting conditions and after a standard high-fat breakfast-separated by a 7-day washout period, Blood samples for determination of alprazolam pharmacokinetics were collected by venipuncture up to 72 hours after dosing. A validated liquid chromatography with tandem mass spectrometry detection method was used to quantify the alprazolam plasma concentration. The overall extent of alprazolam absorption from the ODT formulation, as measured by area under the concentration-time curve, was unaffected during fed conditions. However, the rate of alprazolam absorption was slower after administration during fed relative to fasted conditions. The mean maximum observed plasma concentration (Cmax) decreased approximately 25%, and time to Cmax (Tmax) was delayed approximately 1.5 hours when food was administered before dosing. Coadministration of food was shown to have no effect on extent of absorption of immediate-release alprazolam ODT 1.0 mg when compared with drug administration in the fasted condition; however, the rate of drug absorption was decreased. The clinical significance of the difference in rate of alprazolam absorption is unknown but thought to be minimal.

Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects

Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.

Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme.

St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism. Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St John's wort. Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St John's wort administration, participants were given the probe drugs along with 1 St John's wort tablet to establish postadministration CYP activity; the St John's wort dosing regimen was continued for 48 hours. Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity. A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St John's wort administration (P =.26). A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.

Sublingual administration of alprazolam: a pharmacokinetic approach

A rapid onset of drug action is desirable for patients experiencing panic attacks or episodes of acute anxiety. The aim of this single-dose, three-sequence, crossover study was to investigate the pharmacokinetics of the anxiolytic alprazolam after administration of a single 0.5 mg dose of the drug, in tablets designed for sublingual administration (Tranquinal sublingual; Laboratorios Bago, test product, Ts) compared with oral (Ro) and sublingual (Rs) administration of 0.5 mg of alprazolam of a reference product (Xanax; Pharmacia Upjohn) manufactured for standard oral administration. Blood samples were taken at 0 (before) and 4, 6, 8, 10, 12, 15, 20, 30, 45, 60, 120, 180 and 240 min and 30 h after drug administration, and plasma concentrations of alprazolam were determined by high performance liquid chromatography. The area under the time-concentration curve (AUC) over 0 to 15 min (ng ml−1 hr−1) was 0.12±0.03 for Ts, 0.07±0.03 for Ro and 0.05±0.02 for Rs (P<0.05). The AUC0–4 h values were 22.09±1.96; 22.50±0.99 and 19.65±0.95 for Ts, Ro and R s, respectively, and the AUC0–30 h values were 109.05±12.21, 121.30±4.82 and 111.28±4.87 for Ts, Ro and Rs, respectively. C max values were 6.79±0.85, 7.11±0.64 and 6.14±0.30 ng/ml for Ts, Ro and Rs, respectively, whereas the Tmax was 2 h for all three. The results suggest that measurable plasma concentrations of the sublingual test product are achieved more rapidly than with oral or sublingual administration of a standard reference preparation of alprazolam, which might have therapeutic advantages.

The effect of coadministration of fluvoxamine on plasma concentration of alprazolam and etizolam

The effect of coadministration of fluvoxamine on plasma concentration of alprazolam and etizolam

Therapeutic drug monitoring of alprazolam in adolescents with asthma.

Children and adolescents with severe asthma frequently experience anxiety or depression with anxiety, which can undermine their response to treatment. In addition, these patients often receive theophylline and a variety of adrenergic stimulants, which can exacerbate or worsen anxiety. Such children occasionally are candidates for treatment with anxiolytic therapy. There is a paucity of drug disposition data in adolescents for benzodiazepines, the most frequently used antianxiety drugs. The authors monitored the steady state alprazolam plasma concentration in six children with severe asthma who were administered standard doses of alprazolam. In one patient administered concurrent therapy with troleandomycin, a recognized cytochrome 3A4 inhibitor, alprazolam plasma concentration was markedly elevated. Overall, the disposition data of alprazolam was consistent with data previously reported in adults. Alprazolam appeared to be safe and effective for use in adolescents with asthma.

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

The effect of carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics of alprazolam was examined in a double-blind, randomized crossover study with two phases. Seven healthy male subjects took carbamazepine 300 mg/day or matched placebo orally for 10 days, and on the 8th day they took a single oral 0.8 mg dose of alprazolam. Blood samples were taken and psychomotor function was assessed by the Digit Symbol Substitution Test, Visual Analog Scale, and UKU Side Effect Rating Scale up to 48 h after alprazolam dosing. Carbamazepine significantly (p < .01 to .001) decreased the plasma alprazolam concentrations during the elimination phase. Carbamazepine significantly (p < .001) increased the apparent oral clearance (0.90 ± 0.21 vs. 2.13 ± 0.54 ml/min/kg) and shortened the elimination half-life (17.1 ± 4.9 vs. 7.7 ± 1.7 h), with no significant effect on the peak plasma concentration (11.7 ± 1.5 vs. 13.0 ± 3.5 ng/ml). The majority of psychomotor function parameters during the carbamazepine treatment were not significantly different from those during the placebo treatment, probably because of the sedative effect of carbamazepine itself. The present study suggests that carbamazepine decreases plasma concentration of alprazolam by inducing its metabolism. It also supports the previous studies, suggesting that alprazolam is metabolized predominantly by CYP3A4.

Carbamazepine decreases the plasma concentration of alprazolam

Carbamazepine decreases the plasma concentration of alprazolam

Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence.

The potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, tricyclic antidepressants and benzodiazepines. Many psychotropic medications have an affinity for the cytochrome P450 (CYP) enzymes which promote elimination by transforming lipid soluble substances into more polar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro studies provide a screening method for evaluating drug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predicting these metabolic kinetic drug interactions, case reports and controlled experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evaluating the clinical significance of a potential interaction including: (a) the nature of each drugs' activity at an enzyme site (substrate, inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic routes); (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme activity of the individual, phenotyping/genotyping information; (i) the level of risk of the individual experiencing adverse effects (e.g. the elderly) and (j) from an epidemiological perspective, the probability of concurrent use. This paper systematically reviews both the in vitro and in vivo evidence for drug interactions between SSRIs and other CNS drugs. As potent inhibitors of CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma concentrations of antipsychotic medications metabolised through this enzyme, including perphenazine, haloperidol, thioridazine and risperidone in patients who are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, resulting in higher plasma concentrations. Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase the plasma concentrations of secondary and tertiary tricyclic antidepressants. Sertraline and citalopram are less likely to have this effect. Fluvoxamine can increase the plasma concentrations of tertiary TCAs. Fluvoxamine inhibits, via CYP3A. CYP2C19 and CYP1A2, the metabolism of several benzodiazepines, including alprazolam, bromazepam and diazepam. Fluoxetine increases the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildely to moderately at usual therapeutic doses. Therefore the potential for interactions is less; however, the in vivo evidence is minimal. Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines. The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carb

Pharmacokinetics of alprazolam in elderly patients with multiple diseases.

The pharmacokinetics of alprazolam (1 mg p.o.) were investigated (using a new developed HPLC-assay) in 10 multimorbid elderly patients (five female, five male; mean age 72.8 +/- 8.2 years, creatinine clearance 63.6 +/- 25.9 ml/min, weight 68.9 +/- 13.9 kg). Compared with young and elderly volunteers from other studies peak plasma concentrations of alprazolam were decreased while peak time and elimination half-life were increased. 'Second peak' plasma levels (correlated with age and creatinine clearance) occurred in eight of 10 elderly patients. The variability associated with the pharmacokinetic parameters in the multimorbid elderly patients was far greater than that observed in young and old healthy volunteers. Mean alprazolam concentrations in multimorbid patients aged 72 years or more were elevated as compared to 'younger' patients (age range: 63-71 years). Dose reduction should be considered in the older multimorbid patients.

Venlafaxine and metabolites are very weak inhibitors of human cytochrome P450-3A isoforms

Cytochrome P450-3A isoforms mediate the metabolism of a large number of drugs used in clinical practice (Harvey and Preskom 1996; Ketter et al 1995; yon Moltke et al 1995b). The class of selective serotonin reuptake inhibitor (SSRI) antidepressants has the capacity to inhibit reversibly the activity of human cytochrome P450-3A isoforms, accounting for a number of pharmacokinetic drug interactions. Cotreatment with fluoxetine, for example, impairs metabolic clearance and/or elevates steadystate plasma concentrations of P450-3A substrates such as diazepam, alprazolam, amitriptyline, imipramine, and carbamazepine (Greenblatt et al in press). The inhibitory activity of fluoxetine appears to be attributable mainly to its metabolite, norfluoxetine. Fluvoxamine also is a P450-3A inhibitor, causing pharmacokinetic interactions with alprazolam (Fleishaker and Hulst 1994), diazepam (Perucca et al 1994), and haloperidol (Daniel et al 1994). The antidepressant nefazodone, which produces presynaptic serotonin and norepinephrine reuptake inhibition and postsynaptic serotonin (5-HT) 2 receptor blockade (Ellingrod and Perry 1995), is a reasonably potent 3A inhibitor (von Moltke et al 1996b), significantly elevating plasma concentrations of alprazolam (Greene et al 1995) and triazolam (Barbhaiya et al 1995) when coadministered with these drugs. The antidepressant venlafaxine (VF) acts by blocking reuptake

Alterations in Pharmacodynamics of Anxiolytics in Abstinent Alcoholic Men: Subjective Responses, Abuse Liability, and Electroencephalographic Effects of Alprazolam, Diazepam, and Buspirone

Subjective responses, including those associated with abuse liability and changes in frontal electroencephalographic activity, were assessed in abstinent alcoholic men and control subjects after administration of alprazolam, diazepam, buspirone, and placebo. Plasma concentrations of alprazolam, diazepam, and desmethyldiazepam also were determined. Abuse liability scales were elevated for alcoholic participants above control levels after alprazolam and diazepam. Areas under the concentration-time curve differed only for desmethyldiazepam, which was lower for the alcoholic participants. Compared with control subjects, alcoholic participants had greater declines in the absolute power of the alpha band after diazepam challenge. Alcoholic participants, unlike control subjects, had areas under the effect-time curve for alpha and theta bands that were lower after administration of alprazolam or diazepam than they were after receiving placebo. These results suggest that alprazolam and diazepam are more likely to be abused by alcoholic men than by nonalcoholic men and that alcoholic men have enhanced sensitivity to the effects of benzodiazepines on alpha and theta activity.

A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism*

To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo. Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale. Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.

Pharmacokinetic and dynamic correlates of intravenous alprazolam challenge

The concentration-effect relationship of alprazolam plasma concentration and growth hormone changes was studied in six healthy volunteers by use of three different intravenous bolus doses of alprazolam (0.003, 0.007, and 0.02 mg/kg) in a random blind order. There was a linear increase in peak concentration (Cmax) and area under the curve (AUC) of alprazolam with increasing dose (r = 0.96). There was no significant correlation between alprazolam Cmax and effect on growth hormone measured as either maximum increase or maximum percentage change from baseline. There was, however, an overall positive correlation (r = 0.58) between the AUC values of alprazolam and growth hormone from 0 to 120 minutes, although the relative degree of increased AUC of growth hormone with increasing AUC of alprazolam varied greatly across individuals. The difficulties of interpreting the mechanisms underlying differential growth hormone responses even when concentration of stimulus is controlled are discussed.

Functional tolerance to alprazolam-induced neurologic deficits in mice

Tolerance to alprazolam-induced neurologic deficits was assessed in mice by a rotarod test. Tolerance was found following a second administration of 2 mg/kg alprazolam 24 h after the first dose and it decayed gradually over a period of several weeks. Brain and plasma concentrations of alprazolam indicated that this tolerance was functional.