In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions

The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with Ki values of 8.40, 0.08 and 0.39 microM, respectively. However, the Ki for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.     

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.     

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.     

In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions

1. The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam.

2. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam.

3. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with K_i values of 8.40, 0.08 and 0.39?μM, respectively. However, the K_i for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam.

4. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ.     

Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam

Objective: Grapefruit juice (GFJ) inhibits cytochrome P450 (CYP) 3A4 in the gut wall and increases blood concentrations of CYP3A4 substrates by the enhancement of oral bioavailability. The effects of GFJ on two benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C9), were determined in this study. Methods: The study consisted of four separate trials in which nine healthy subjects were administered 0.25 mg triazolam or 15 mg quazepam, with or without GFJ. Each trial was performed using an open, randomized, cross-over design with an interval of more than 2 weeks between trials. Blood samples were obtained during the 24-h period immediately following the administration of each dose. Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and utilizing a visual analog scale. Results GFJ increased the plasma concentrations of both triazolam and quazepam and of the active metabolite of quazepam, 2-oxoquazepam. The area under the curve (AUC)(0–24) of triazolam significantly increased by 96% (p<0.05). The AUC(0–24) of quazepam (+38%) and 2-oxoquazepam (+28%) also increased; however, these increases were not significantly different from those of triazolam. GFJ deteriorated the performance of the subjects in the DSST after the triazolam dose (−11 digits at 2 h after the dose, p<0.05), but not after the quazepam dose. Triazolam and quazepam produced similar sedative-like effects, none of which were enhanced by GFJ. Conclusion These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9.     

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 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.     

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.     

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.     

Drug interaction between St John's Wort and quazepam

AIM: St John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined. METHODS: Thirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day(-1)) or placebo for 14 days. The study was performed in a randomized, placebo-controlled, cross-over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14. RESULTS: SJW decreased the plasma quazepam concentration. The Cmax and AUC(0-48) of quazepam after SJW were significantly lower than those after placebo [Cmax; -8.7 ng ml(-1) (95% confidence interval (CI) -17.1 to -0.2), AUC0-48; -55 ng h ml(-1) (95% CI -96 to -15)]. The urinary ratio of 6beta-hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85-3.4)). Quazepam, but not SJW, produced sedative-like effects in the VAS test (drowsiness; P < 0.01, mental slowness; P < 0.01, calmness; P < 0.05, discontentment; P < 0.01). On the other hand, SJW, but not quazepam impaired psychomotor performance in the DSST test. SJW did not influence the pharmacodynamic profile of quazepam. CONCLUSIONS: These results suggest that SJW decreases plasma quazepam concentrations, probably by enhancing CYP3A4 activity, but does not influence the pharmacodynamic effects of the drug.     

Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects

AIMS: Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. METHODS: The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day-1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. RESULTS: Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml-1 h to 7011 ng ml-1 h (P < 0.001) and the elimination half-life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml-1 vs 109 ng ml-1, P < 0.001). CONCLUSIONS: Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.     

Excretion of quazepam into human breast milk

Previous metabolic studies have established that two major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15-mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2-oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam through 48 hours was only 0.11 per cent.     

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.     

Effect of itraconazole on the pharmacokinetics of imidafenacin in healthy subjects

The effect of itraconazole, a potent inhibitor of the CYP3A isoenzyme family, on the pharmacokinetics of imidafenacin, a novel synthetic muscarinic receptor antagonist, was investigated. Twelve healthy subjects participated in this open-label, self-controlled study. In period I, subjects received a single oral dose of 0.1 mg imidafenacin. In period II, they received multiple oral doses of 200 mg itraconazole for 9 days and a single oral dose of 0.1 mg imidafenacin on day 8. Plasma concentrations of imidafenacin and M-2, the major metabolite of imidafenacin metabolized by CYP3A4, were determined. Analytes were measured by liquid chromatography tandem mass spectrometry. Following coadministration with itraconazole, the maximum plasma concentration (C(max)) of imidafenacin increased 1.32-fold (90% confidence intervals [CIs]: 1.12-1.56), and the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased 1.78-fold (90% CI: 1.47-2.16). In conclusion, itraconazole increases the plasma concentrations of imidafenacin by inhibiting CYP3A4. Therefore, itraconazole or potent CYP3A4 inhibitors should be carefully added to imidafenacin drug regimens.     

Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite

Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC_0–t) and the peak concentration of oxybutynin twofold. The AUC_0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance. Received: 29 October 1996 / Accepted in revised form: 13 February 1997     

Disposition and metabolic fate of 14C-quazepam in man

The absorption, metabolism, and excretion of quazepam, a new benzodiazepine hypnotic, was investigated in six normal male volunteers after oral administration of 25 mg 14C-quazepam in solution. Quazepam was well absorbed. Plasma radioactivity peaked (324.6 ng quazepam eq/ml) 1.75 hr postdose. Unchanged quazepam reached its maximum plasma level (148 ng/ml) at 1.5 hr with an apparent absorption half-life of 0.4 hr. Major plasma metabolites of quazepam were 2-oxoquazepam (OQ), obtained by replacement of S by O,N-desalkyl-2-oxoquazepam (DOQ), and 3-hydroxy-2-oxoquazepam (HOQ) glucuronide. Both OQ and DOQ are pharmacologically active. Plasma elimination half-lives for quazepam, OQ, DOQ, and radioactivity were 39, 40, 69, and 76 hr, respectively. The respective AUC (120 hr) values were 715, 438, 3323, and 11402 hr X ng/ml. Approximately 54% of the radioactive dose was excreted in the urine (31.3%) and feces (22.7%) over a 5-day period. HOQ glucuronide was the major urinary metabolite of quazepam. Other metabolites present in the urine in relatively large amounts were glucuronides of DOQ and HDOQ.     

Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam

AIMS: There is little information on interaction between food and the hypnotic agent quazepam. We therefore studied the effects of food and its time interval on the pharmacokinetics and pharmacodynamics of quazepam. METHODS: A randomized three-phase crossover study with 2-week intervals was conducted. Nine healthy male volunteers took a single oral 20 mg dose of quazepam under the following conditions: 1) after fasting overnight; 2) 30 min after eating standard meal; or 3) 3 h after eating the same meal. Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam and psychomotor function using the Digit Symbol Substitute Test (DSST), Stanford Sleepiness Scale (SSS) and Visual Analogue Scale were measured up to 48 h. RESULTS: During the food treatments at 30 min and 3 h before dosing, the peak concentrations (Cmax) were 300% (95% CI 260, 340%; P < 0.001) and 250% (95% CI 210, 290%; P < 0.01) of the corresponding value during the fasting phase. For quazepam, the area under the plasma concentration-time curve from 0 to 8 h measured at 30 min and 3 h before dosing was significantly increased, with the food treatments by 2.4-fold (95% CI 2.0; 2.8-fold; P < 0.001) and 2.1-fold (95% CI 1.7; 2.4-fold; P < 0.01), respectively. In response to pharmacokinetic changes, some of the pharmacodynamics (DSST, P < 0.05; SSS, P < 0.05) differed significantly between fasted status and fed status. No difference was found in any pharmacokinetic or pharmacodynamic parameters between the two food treatment phases. CONCLUSIONS: A food effect on quazepam absorption is evident and continues at least until 3 h after food intake. The dosing of quazepam after a long period of ordinary fasting might reduce its efficacy because a 3 h interval between the timing of the evening meal and bedtime administration of hypnotics is regarded as normal in daily life.     

The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel

AIMS: Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4). METHODS: This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose. RESULTS: Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel. CONCLUSIONS: According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.     

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.     

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.