Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double-blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration-time curve of 2-oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.     

Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200?mg/day or matched placebo orally for 6 days took an oral 0.8?mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48?h after alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersøgelser side effect rating scale. Itraconazole significantly (P?相似文献   

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.     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam

AIMS: To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. METHODS: In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale. RESULTS: Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 +/- 4.3 vs 3.91 +/- 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 +/- 10.8 vs 68.71 +/- 24.1 ng ml h(-1)), and prolonged the elimination half-life (4.56 +/- 1.4 vs 23.27 +/- 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item 'sleepiness' of UKU (P < 0.05) were significantly decreased. CONCLUSIONS: Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.     

Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism

Objective To clarify the involvement of cytochrome P₄₅₀ (CYP) 3A4 in the metabolism of etizolam.Methods The effects of itraconazole, a potent and specific inhibitor of CYP3A4, on the single oral dose pharmacokinetics and pharmacodynamics of etizolam were examined. Twelve healthy male volunteers received itraconazole (200 mg/day) or placebo for 7 days in a double-blind randomized crossover manner, and on the 6th day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function using the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured by means of high-performance liquid chromatography.Results Itraconazole treatment significantly increased the total area under the plasma concentration–time curve (AUC; 213±106 ngh/ml versus 326±166 ngh/ml, P<0.001) and the elimination half-life (12.0±5.4 h versus 17.3±7.4 h, P<0.01) of etizolam. The 90% confidence interval of the itraconazole/placebo ratio of the total AUC was 1.38–1.68, indicating a significant effect of itraconazole. No significant change was induced by itraconazole in the two pharmacodynamic parameters.Conclusion The present study suggests that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved in etizolam metabolism.     

Interaction study between fluvoxamine and quazepam

It has been reported that fluvoxamine, an inhibitor of various cytochrome P450 enzymes, markedly inhibits the metabolism of several drugs. The purpose of the present study was to examine a possible interaction between fluvoxamine and quazepam. Twelve healthy male volunteers received fluvoxamine 50 mg/day or placebo for 14 days in a double-blind randomized crossover manner, and on the 4th day they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after quazepam dosing. Plasma concentrations of quazepam and its active metabolites 2-oxoquazepam (OQ) and N-desalkyl-2-oxoquazepam (DOQ) were measured by high-performance liquid chromatography (HPLC). Fluvoxamine did not change plasma concentrations of quazepam but significantly decreased those of OQ from 6 to 12 hours and those of DOQ from 3 to 48 hours. The AUC ratio of OQ to quazepam was significantly lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function at most of the time points. The present study suggests that fluvoxamine slightly inhibits the metabolism of quazepam to OQ, but this interaction appears to have minimal clinical significance.     

Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo

OBJECTIVE: To study the effects of methylprednisolone on the pharmacokinetics and pharmacodynamics of triazolam. METHODS: In this three-phase cross-over study, ten healthy subjects received 0.25 mg oral triazolam on three occasions: on day 1 (no pretreatment, control), on day 8 (1 h after a single dose of 32 mg oral methylprednisolone) and on day 18 (after further treatment with 8 mg oral methylprednisolone daily for 9 days). The plasma concentrations of triazolam were determined up to 10 h, and its effects were measured using four psychomotor tests up to 6 h. RESULTS: The single dose of methylprednisolone showed no significant effects on the pharmacokinetics of triazolam. However, the Digit Symbol Substitution Test result was better (P < 0.05) during the single-dose methylprednisolone phase than during the control phase, the other three tests showing no differences between the phases. The multiple-dose treatment with methylprednisolone reduced the mean peak plasma concentration (Cmax) of triazolam by 30% (P < 0.05) but had no significant effects on the time to Cmax (tmax), elimination half-life (t 1/2), area under the plasma concentration-time curve from 0 h to 10 h (AUC(0-10 h)) and AUC(0-infinity) and did not alter the effects of triazolam. CONCLUSION: A single, relatively high dose of methylprednisolone (32 mg) did not affect cytochrome P450 (CYP)3A4 activity, and treatment with 8 mg methylprednisolone daily for 9 days did not result in clinically significant induction of CYP3A4.     

Rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam

The purpose of the present study was to examine the effects of rifampicin on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. Thirteen healthy male volunteers received rifampicin 450 mg/day, or matched placebo, for 7 days in a double-blind randomized crossover manner. On the sixth day they received a single oral 0.5-mg dose of brotizolam, and blood sampling was performed for 24 hours, together with an assessment of psychomotor function using the Digit Symbol Substitution Test and the Stanford Sleepiness Scale. Rifampicin treatment significantly (P<0.001) decreased the peak plasma concentration (69%), total area under the plasma concentration-time curve (90%) and elimination half-life (79%) of brotizolam. Rifampicin significantly increased the area under the score-time curve of the Digit Symbol Substitution Test (P<0.01), and decreased that of the Stanford Sleepiness Scale (P<0.05). The present study suggests that rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam and, therefore, this combination is not recommended in clinical practice.     

Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers.

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration-time curve six-fold (P < 0.001), the peak concentration 2.5-fold (P < 0.001) and the elimination half-life two-fold (P < 0.001) compared with placebo and terbinafine pretreatments. The pharmacokinetic parameters did not differ between placebo and terbinafine phases. The higher concentrations of midazolam during the itraconazole phase were associated with increased effects. In contrast to itraconazole, terbinafine had no effect on midazolam pharmacokinetics and psychomotor performance tests were unchanged from placebo.     

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers

Rationale and objective Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P ₄₅₀ (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam.Methods Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration.Results Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (±SD) values of area under the plasma concentration–time curve and elimination half-life for placebo versus itraconazole were 1328±330 ng h/ml versus 1445±419 ng h/ml and 32.1±9.3 h versus 31.1±8.4 h, respectively.Conclusion The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors.     

Effects of itraconazole and tandospirone on the pharmacokinetics of perospirone

Perospirone is an atypical antipsychotic agent originated and clinically used in Japan. Based on an in vitro study, it is reported that perospirone is mainly metabolized to ID-15036 by cytochrome P450 (CYP) 3A4. In this study, the authors investigated the effects of itraconazole, which is a specific inhibitor of CYP3A4, or tandospirone, which is mainly metabolized by CYP3A4 and is expected to competitively inhibit the activity of this enzyme, on single oral dose pharmacokinetics of perospirone. After pretreatment with 200 mg daily of itraconazole or 10 mg daily of tandospirone for 5 days, 9 healthy male subjects received 8 mg of perospirone. Plasma concentrations of perospirone and ID-15036 up to 10 hours after perospirone dosing were measured by high-performance liquid chromatography (HPLC). The metabolism of perospirone was significantly inhibited by treatment with itraconazole but not by tandospirone. The present study suggests that CYP3A4 is significantly involved in metabolism of perospirone in humans.     

Selegiline pharmacokinetics are unaffected by the CYP3A4 inhibitor itraconazole

OBJECTIVE: To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers. METHODS: In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes. RESULTS: Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P < 0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r = 0.41; P < 0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline. CONCLUSIONS: The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors.     

Fluvoxamine affects sildenafil kinetics and dynamics

Sildenafil used as oral drug treatment for erectile dysfunction is predominantly metabolized by the cytochrome P450 isozyme 3A4. The antidepressant fluvoxamine is an inhibitor of cytochrome P450 3A4. In a randomized, double-blind, placebo-controlled, crossover study, we evaluated the effects of fluvoxamine dosed to steady state on the pharmacokinetics and pharmacodynamics of sildenafil. Twelve healthy men received oral fluvoxamine or placebo for 10 days (50 mg every day on days 1-3; 100 mg every day on days 4-10). On day 11, all participants received a single, oral, open-label dose of 50 mg sildenafil, and blood samples were collected for analysis of sildenafil plasma concentrations by liquid chromatography/mass spectrometry. Concurrently, the effect of sildenafil on venodilation induced by a constant dose of sodium nitroprusside was assessed using the dorsal hand vein compliance technique. Sildenafil was well tolerated in the presence of fluvoxamine. During fluvoxamine, sildenafil exposure (area under the curve) significantly increased by 40% (P < 0.001), and its half-life increased by 19% (P = 0.034). Concurrently, sodium nitroprusside-induced venodilation was significantly augmented by 59% during fluvoxamine compared to placebo (P = 0.012). In conclusion, sildenafil kinetics are mildly affected by fluvoxamine which translates into an increase in vascular sildenafil effects. Whereas the pharmacokinetic changes do not suggest a large clinically relevant interaction, it may be prudent to consider a starting dose of 25 mg in patients concurrently treated with fluvoxamine.     

Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine

Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) by 60% (P<0.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.     

Inhibition of the metabolism of brotizolam by erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism

AIMS: To obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam. METHODS: Fourteen healthy male volunteers received erythromycin 1200 mg day(-1) or placebo for 7 days in a double-blind randomized crossover manner. On the 6th day they received a single oral 0.5-mg dose of brotizolam, and blood samplings were performed for 24 h. RESULTS: Erythromycin treatment significantly increased the peak plasma concentration (P < 0.05), total area under the plasma concentration-time curve (P < 0.01), and elimination half-life (P < 0.01) of brotizolam. CONCLUSIONS: The present study provides in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism.     

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

BACKGROUND AND AIMS: Gemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, infinity)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. METHODS: In a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. RESULTS: During the gemfibrozil-itraconazole phase, the AUC(0, infinity) and C(max) of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range - 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t(max) and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. CONCLUSIONS: The combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.     

Effects of itraconazole or grapefruit juice on the pharmacokinetics of telithromycin

STUDY OBJECTIVE: To determine whether coadministration of the cytochrome P450 3A4 (CYP3A4) inhibitors itraconazole or grapefruit juice will modify the pharmacokinetic profile of telithromycin, and to assess the safety of telithromycin. DESIGN: Two single-center, open-label studies; the itraconazole study was nonrandomized, sequential, and multiple dose, and the grapefruit juice study was randomized, two-period crossover, and single dose. SETTING: Two clinical investigative centers in the United States. SUBJECTS: Thirty-four healthy, nonsmoking male volunteers aged 18-45 years. INTERVENTION: All patients received telithromycin 800 mg/day; 18 patients received concomitant itraconazole 200 mg/day, and 16 received concomitant single-dose, single-strength grapefruit juice. MEASUREMENTS AND MAIN RESULTS: Standard pharmacokinetic and safety measurements were performed. Itraconazole given concomitantly with telithromycin increased the steady-state area under the plasma concentration-time curve from 0-24 hours of telithromycin by 53.8% (p<0.0001). Coadministration of grapefruit juice did not affect telithromycin pharmacokinetic parameters, and telithromycin was well tolerated in both studies. CONCLUSION: Only modest changes in the pharmacokinetics of telithromycin were seen with concomitant administration of itraconazole. Telithromycin pharmacokinetics were unaffected by concomitant administration of grapefruit juice.     

Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam

The effects of repeated ingestion of grapefruit juice, an inhibitor of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of both single and multiple oral doses of alprazolam, a substrate of CYP3A4, were examined. In study 1, eight healthy volunteers ingesting 600 ml/day water or grapefruit juice for 10 days took a single oral 0.8-mg dose of alprazolam on the eighth day. Plasma drug concentrations were monitored up to 48 h after alprazolam dosing together with evaluation of psychomotor function. Grapefruit juice altered neither the plasma concentrations of alprazolam at any time points, any pharmacokinetic parameters, nor the majority of psychomotor function parameters in subjects. In study 2, 11 patients with anxiety disorders receiving alprazolam (0.8-2.4 mg/day) ingested grapefruit juice (600 ml/day) for 7 days. Blood samples were collected before and during grapefruit juice ingestion and 1 week after its discontinuation together with an assessment of clinical status. Grapefruit juice altered neither the steady-state plasma concentration of alprazolam nor the clinical status in patients. The present study shows that grapefruit juice is unlikely to affect pharmacokinetics or pharmacodynamics of alprazolam due to its high bioavailability.     

Effect of itraconazole on the pharmacokinetics of inhaled lidocaine

Lidocaine is metabolized by cytochrome P450 3A4 and 1A2 enzymes (CYP3A4 and CYP1A2) in vitro. However, their relative contribution to the elimination of lidocaine depends on lidocaine concentration. We have studied the effect of a potent CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of inhaled lidocaine in ten healthy volunteers using a randomized, two-phase cross-over study design. The interval between the phases was four weeks. The subjects were given orally itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject inhaled a single dose of 1.5 mg/kg of lidocaine by nebulizer. Plasma samples were collected until 10 hr and the concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured by gas chromatography. The areas under the lidocaine and monoethylglycinexylidide concentration time curves were similar during both phases. No statistically significant differences were observed in any of the pharmacokinetic parameters; peak concentrations, concentration peak times or elimination half-lives of lidocaine or monoethylglycinexylidide. The clinical implication of this study is that no lidocaine dosage adjustments are necessary if it is used to prepare the airway prior to endoscopic procedures or intubation in patients using itraconazole or other inhibitors of CYP3A4.     

Induction of the metabolism of etizolam by carbamazepine in humans

Objective To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam.Methods Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography.Results Carbamazepine treatment significantly decreased the peak plasma concentration (17.5±4.1 ng/ml versus 13.9±4.1 ng/ml; P<0.05), total area under the plasma concentration–time curve (194.8±88.9 ng h/ml versus 105.9±33.0 ng h/ml; P<0.001), and elimination half-life (11.1±4.6 h versus 6.8±2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters.Conclusions The present study suggests that carbamazepine induces the metabolism of etizolam.