Effects of itraconazole on the steady-state plasma concentrations of bromperidol and reduced bromperidol in schizophrenic patients.

RATIONALE: A previously reported pharmacokinetic interaction between bromperidol and carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, suggests possible involvement of CYP3A4 in the metabolism of bromperidol. OBJECTIVE: We investigated pharmacokinetic interaction between bromperidol and itraconazole, a potent inhibitor of CYP3A4, to clarify the involvement of CYP3A4 in the metabolism of bromperidol and its reduced metabolite. METHODS: Itraconazole 200 mg/day for 7 days was coadministered to eight schizophrenic patients treated with a fixed dose of bromperidol 12 or 24 mg/day for at least 2 weeks. Blood samples were taken before and 1 week after itraconazole coadministration and 1 week after its discontinuation, together with clinical assessments using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale. RESULTS: Plasma concentrations of bromperidol during itraconazole coadministration (16.7+/-4.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (8.9+/-4.4 ng/ml) and 1 week after its discontinuation (9.9+/-4.3 ng/ml). Plasma concentrations of reduced bromperidol during itraconazole coadministration (3.6+/-2.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (1.8+/-1.3 ng/ml). No changes were observed in BPRS and UKU scores throughout the study. CONCLUSIONS: The pharmacokinetic interaction between bromperidol and itraconazole is probably due to the inhibitory effect of itraconazole on the metabolism of bromperidol. This study provides in vivo evidence of involvement of CYP3A4 in the metabolism of bromperidol and reduced bromperidol.

Characteristics and risk factors of acute dystonia in schizophrenic patients treated with nemonapride, a selective dopamine antagonist.

The occurrence of acute dystonia was prospectively monitored in 39 schizophrenic patients (18 male and 21 female) treated with 9 to 27 mg/day of nemonapride, a selective dopamine antagonist, and the relationship of acute dystonia with characteristics of patients and plasma concentrations of the drug and prolactin was investigated. Twenty (51.3%) of 39 patients had dystonic reactions, the onsets of which occurred within 3 days after the initiation of treatment in 90% of dystonic patients. The incidence of acute dystonia was significantly higher in male than in female patients (77.8% vs. 28.6%, p < 0.05). Younger male patients (< or = 30 years) especially had an extremely high incidence of this side effect (91.7%). A positive correlation between prolactin response after 1 week of treatment and dystonia rating scores was found in male (Spearman rank correlation: r(s) = 0.606,p < 0.01) but not in female patients (r(s) = -0.378,p = not significant). These results suggest that young male patients have the highest risk of neuroleptic-induced dystonia. Prolactin response after 1 week of treatment as an index of dopamine blockade may reflect vulnerability to the development of acute dystonia at least in male patients treated with nemonapride.

Effects of various factors including the CYP2D6 genotype and coadministration of flunitrazepam on the steady-state plasma concentrations of bromperidol and its reduced metabolite.

The effects of various factors, including the cytochrome P450 (CYP) 2D6 genotype and the coadministration of flunitrazepam, on the steady-state plasma concentrations (Css) of bromperidol and its reduced metabolite were studied in 62 schizophrenic inpatients receiving bromperidol 12 mg/day. By use of allele-specific PCR analysis, the wild type allele (CYP2D6*1A) and four mutated alleles causing either absent (CYP2D6*3, CYP2D6*4 and CYP2D6*5) or decreased (CYP2D6*10) CYP2D6 activity were identified. The means (ranges) of the Css of bromperidol and reduced bromperidol corrected to the median body weight were 7.2 (1.3-17.4) and 2.2 (0.4-8.9) ng/ml, respectively. Neither the Css of bromperidol nor that of reduced bromperidol significantly differed among the patients with no (n = 28), one (n = 30) and two mutated alleles (n = 4). The patients coadministered with flunitrazepam (n = 52) had significantly (P < 0.05) higher Css of bromperidol, but not reduced bromperidol, than those not (n = 10). Age, sex and smoking had no significant effects on the Css of these compounds. The present study thus suggests that the polymorphic CYP2D6 is not involved in the metabolism of bromperidol and reduced bromperidol to a major extent. The coadministration of flunitrazepam inhibits the metabolism of bromperidol, but age, sex and smoking do not affect it.

Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects.

The authors investigated the single oral dose kinetics of zotepine and its relationship with prolactin response and side effects in 14 healthy male volunteers. Each subject took a single oral 25-mg dose of zotepine, and plasma concentrations of zotepine, prolactin, and their side effects were monitored up to 36 hours after dosing. The means +/- SD of the time of maximal plasma concentration (tmax), the apparent oral clearance, the apparent volume of distribution, and the elimination half-life (t1/2) were 3.8 +/- 1.2 hours, 4.6 +/- 4.2 1/h.kg, 109.0 +/- 59.0 1/kg, and 21.0 +/- 8.9 hours, respectively. The change in prolactin concentrations and side effect scores were parallel with that of drug concentrations, although no significant correlation was found between these three parameters at any time-point. The current results clearly indicate that the tmax and t1/2 of zotepine are much longer than those previously reported, which are reflected in the changes in prolactin concentrations and side effect scores.

Plasma concentrations of trazodone and m-chlorophenylpiperazine at steady state can be predicted from those after an initial dose of trazodone.

1. The authors studied the correlations between plasma concentrations of trazodone and mCPP at steady state and those after an initial dose of trazodone. 2. Fifteen depressed patients received trazodone 150 mg at bedtime for 3 weeks, and blood samplings were taken 12 h after the initial dose and 12 h after the last dose at each week. Plasma concentrations of trazodone and mCPP were measured by high-performance liquid chromatography. 3. Plasma concentration of mCPP, but not trazodone, was significantly higher at each week than after initial dosing. 4. For both trazodone and mCPP, significant linear relationships were found between plasma concentration after initial dosing and the average of 3 weeks' plasma concentrations. 5. The present study thus suggests that plasma concentrations of trazodone and mCPP at steady state can be predicted from those after an initial dose of trazodone.

Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin.

A case of repetitive hallucinations during treatment with a therapeutic dosage of triazolam (0.25 mg/day) and nitrazepam (5 mg/day) is presented. The patient suffered from acute pneumonia and chronic renal failure. Such non-psychotic symptoms as anxiety, tremor and depressed feeling were observed initially. However, after co-administration of erythromycin (600 mg/day), visual hallucinations and abnormal bodily sensations developed repeatedly after each administration of triazolam or nitrazepam. This report suggests that benzodiazepine hypnotics even at a therapeutic dosage with co-administration of erythromycin causes serious psychotic symptoms in vulnerable patients with physical complications.

Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug.

Effects of smoking and cytochrome P450 2C19 (CYP2C19) status on the single dose kinetics of zotepine and pharmacokinetic interaction between zotepine and diazepam were investigated. In 14 healthy volunteers, the pharmacokinetics of zotepine after a single oral 25 mg dose were compared between eight smokers and six non-smokers, or between seven extensive metabolizers (EMs) and seven poor metabolizers (PMs) of S-mephenytoin. There was no significant difference in any pharmacokinetic parameters between smokers and non-smokers, or between the EM and PM groups. In 17 patients treated with zotepine 80-340 mg/day, intra-individual changes in plasma concentrations of zotepine caused by coadministration of diazepam 10 mg/day for 2 weeks were examined. Plasma concentrations of zotepine were significantly increased after coadministration of diazepam (P < 0.05). Consequently, it is suggested that neither smoking nor CYP2C19 status affects the metabolism of zotepine. The elevation in plasma concentrations of zotepine after coadministration of diazepam may be a result of competitive inhibition of zotepine metabolism by diazepam via other isoenzyme than CYP2C19, e.g., CYP3A4.

A method for rapid determination of zotepine by gas chromatography-mass spectrometry.

A rapid and sensitive method using solid-phase extraction and gas chromatography-mass spectrometry (GC-MS) has been developed for the determination of zotepine (ZTP), an atypical neuroleptic, in human plasma. The detection limit of ZTP was 1 microgram/L. Standard curves over the concentration range from 2.5 to 100 micrograms/L had a good linearity. Intraassay variability ranged from 2.2 to 3.3% and interassay variability from 3.5 to 6.6% at the concentration range of 5-75 micrograms/L. Our preliminary data of single-dose kinetics of ZTP by using this method suggested that the peak time and elimination half-life was much longer than previously reported, and that there appeared to be a second peak after 10-12 h of ZTP administration, indicating the possibility of the presence of enterohepatic recirculation.