HUMAN PSYCHOPHARMACOLOGY, VOL. 7,33 1-336 (1992)

Steady-state Serum Kinetics of Zotepine K. OTANI*, T. KONDO, S. KANEKO, T. HIRANO, K. MIHARA, and Y. FUKUSHIMA Department of Neuropsychiatry, Hirosaki University Hospital, Hirosaki, Japan

The steady-state serum kinetics of zotepine, an antipsychotic drug, were studied in 59 psychiatric in-patients receiving 50-500 mg/day (mean 215 mg/day) of the drug. There was a 26-fold inter-individual variation in the concentration/ dose ratios (C/D ratios: ng/ml/mg/kg), which ranged from 2.4 to 62.2 (mean 13.2). The smokers ( n = 37) had signifi- cantly lower C/D ratios (mean fSD: 9.7 * 7.0 vs 19.0 f 1 5 . 5 , ~ < 0.01), while the patients co-administered benzodia- zepines (n = 14) had significantly higher C/D ratios (19.6 f 12.5 vs 11.2 f 10.9, p < 0.01) than the others. There was no significant relationship between the C/D ratios and age or gender. In the 24 cases where the dose was fixed at 100 mg/day in the first week and at 200 mg/day for the next 3 weeks, no significant difference was found in the mean C/D ratios during the 4 weeks. The present study thus suggests a large inter-individual variation in the metabolism of zotepine, and that smoking enhances, and co-administration of benzodiazepines inhibits, the metabolism. Age and gender do not affect the kinetics of the drug. The results also suggest no dose-dependent kinetics and no enzyme-inducing effect of the drug.

KEY woms-Zotepine, serum concentration, steady-state, smoking, benzodiazepine.

INTRODUCTION

Zotepine is an antipsychotic drug developed in Japan. An original animal study (Uchida et al., 1979) showed that the drug had antidopaminergic effects similar to chlorpromazine, while subsequent studies (Yamawaki, 1987; Hirano et al., 1990) showed significant effects on the serotonergic sys- tem. Double-blind trials show that zotepine has an efficacy equivalent to haloperidol in paranoid schi- zophrenia (Fleischhacker et al., 1989), but a higher efficacy in schizophrenia with prevailingly negative symptoms (Barnas et al., 1992). Furthermore, the drug causes fewer neurological side-effects than haloperidol (Fleischhacker et al., 1989; Barnas et al., 1992). All these findings suggest that zotepine is a valuable antipsychotic drug. Nevertheless, the steady-state kinetics of this drug are virtually unknown.

Therefore, the purpose of the present study was to elucidate the steady-state serum kinetics of zote- pine. We analysed not only the effects of age and gender but also those of smoking and co-adminis- tration of benzodiazepines, which are rarely taken into account in the kinetic studies of antipsychotic drugs. In addition, we examined whether or not the drug had dose-dependent kinetics and an enzyme-inducing effect. The study was undertaken as part o fa series of studies on the clinical pharma- cology of zotepine. The lack of significant effects

* Author to whom correspondence should be addressed.

of co-administration of the anticholinergic drugs biperiden and piroheptine on the kinetics of the drug has been reported elsewhere (Otani et al., 1990). The relationships between clinical effects and serum concentrations of the drug will be reported separately.

MATERIALS AND METHODS

The subjects consisted of 59 physically healthy inpatients (33 men, 26 women). Informed consent to participate in this study was obtained from the patients or their families. The diagnosis according to the DSM-111-R criteria was schizophrenia in 47 cases, mental retardation in seven cases, and bipo- lar disorder in five cases. The mean age (and range) was 34 (18-68) years, and the mean body weight 62 (41-102) kg. Thirty-seven cases were smokers (2 10 cigarettedday); none was a heavy drinker.

Zotepine was administered in two or three equally divided doses. The daily doses ranged from 50 to 500 mg (mean 21 5 mg). In 14 cases the follow- ing benzodiazepines were co-administered; fluni- trazepam (2-6 mg/day, seven cases), etizolam (2-3 mg/day, six cases), cloxazolam (6-8 mg/day, two cases), diazepam (6 mg/day, one case), and nitraze- pam (10 mg/day, one case). No other drugs except biperiden and sennoside were given.

In the 24 cases where the relationships between clinical effects and serum concentrations of zote- pine were studied the dose was fixed at 100 mg/day in the first week, and at 200 mg/day for the next

0885-6222/92/05033 146$08.00 0 1992 by John Wiley & Sons, Ltd.

332 K. OTANI ET AL.

Table 1 . Serum concentrations and concentration/dose ratios fC/D ratios) of zotevine in 24 cases

1 week 2 weeks 3 weeks 4 weeks ~~

Serum concentration (ng/ml) 17.2 f 11.2” 38.2 f 36.8 37.8 f 34.2 36.5 f 34.0

C/D ratio (ng/ml/mg/kg) 10.4f 8.2 12.0f 13.1 11.6f11.9 11.3f12.0

’: significantly (p < 0.001) different from other weeks. The values in the table are mean f SD.

3 weeks. In these cases weekly blood samplings were performed at 7 a.m., 12 h after the last dose and before the next morning dose. In the remaining 35 cases, blood samplings were performed 2 4 weeks after initiation of treatment.

Serum concentrations of zotepine were measured in duplicate by gas chromatography (Noda et al., 1979). Statistical analyses were conducted by Fried- man rank test, Tukey test, Wilcoxon rank-sum test, and Spearman rank test; statistically significant values of 0.05 or less are reported.

RESULTS

Table 1 shows the serum concentrations and the serum concentration to dose per body weight ratios (C/D ratios: ng/ml/mg/kg of zotepine during the 4 weeks in the 24 cases. There was no significant difference in the mean C/D ratios during the 4 weeks.

In each of the 24 cases the average of the C/D ratios of the second, third, and fourth weeks was calculated, and these were mixed with the C/D ratios of the remaining 35 cases determined 2 4 weeks after initiation of treatment. There was a 26-fold inter-individual variation in these pooled C/D ratios, that ranged from 2.4 to 62.2 (mean 13.2). The effects of smoking, co-administration of benzodiazepines, age, and gender on the C/D ratios were analysed using the pooled data.

Figure 1 shows the effect of smoking on the C/D ratios. The C/D ratios in the smokers (mean fSD: 9.7 f 7.0) were significantly 0, < 0.01) lower than those in the non-smokers (19.0 rt 15.5). Figure 2 shows the effect of co-administration of benzodia- zepines on the C/D ratios. The C/D ratios in the patients co-administered benzodiazepines (19.6 f 12.5) were significantly 0, < 0.01) higher than those in the others (1 1.2 f 10.9).

There was no significant correlation between age and the C/D ratios (Figure 3). No significant differ- ence was found between the C/D ratios in men (11.6 k 7.3) and those in women (15.1 f 15.6).

DISCUSSION

The single dose kinetics of zotepine, as well as those at steady-state, are not fully understood. The avail- able data suggest that the drug undergoes extensive metabolism; the important metabolic pathways are N-demethylation and hydroxylation and the elimi- nation half-life is about 8 h (Noda et al., 1979). The existence of pharmacologically active metabo- lites has not been reported.

Large inter-individual variations in blood con- centrations in patients receiving the same doses of antipsychotic drugs have been reported (Dysken et al., 1981; Shvartsburd et al., 1983; Alfredsson et al., 1984; Mazure et al., 1990). In line with these, there was a 26-fold variation in the C/D ratios of zotepine, suggesting a large inter-individual varia- tion in the metabolism of the drug. As the main mechanism of this variation, a genetic factor may be involved, since the metabolism of several anti- psychotic drugs, for example chlorpromazine (Inaba et af., 1985), perphenazine (Dahl-Puustinen et af., 1989), levomepromazine (Kallio et al., 1990), thioridazine (von Bahr et al., 1991) and haloperidol (LLerena et al., 1992), is related to the genetically determined debrisoquine/sparteine-type oxidation polymorphism.

Though it has rarely been studied, an interaction between benzodiazepines and antipsychotic drugs is unlikely to occur, since the metabolism of diaze- pam has been shown to be related to the mepheny- toin polymorphism (Bertilsson et al., 1989), which is independent of the debrisoquine/sparteine-type polymorphism (Horai et al., 1989). Therefore, the present results suggesting competitive inhibition of zotepine metabolism by benzodiazepines were rather unexpected. To confirm the present findings, the intra-individual change in serum concen- trations of the drug caused by co-administration of benzodiazepines should be examined in a future study. It may indicate that zotepine is a unique antipsychotic drug from a pharmacogenetic point of view; its metabolism may be associated with the mephenytoin polymorphism.

STEADY-STATE SERUM KINETICS OF ZOTEPINE 333

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Smoklng (-1 Smoking ( + I Figure 1 . in the figure indicate the mean values of each group

The effect of smoking on the concentration/dose ratios (C/D ratios) of zotepine. The horizontal lines

Though smoking interacts with the metabolism of a number of drugs (D'Arcy, 1984), there are few studies on antipsychotic drugs. The available data suggest that it enhances the metabolism of fluphenazine (Ereshefsky et al., 1985), and haloper- idol (Miller et af., 1990). Our result suggests that smoking also enhances the metabolism of zotepine. We suggest that smoking should always be taken into account in kinetic studies of antipsychotic drugs.

The effects of age on the kinetics of antipsychotic

drugs have been inconsistent; a positive correlation between age and blood concentrations has been reported for chlorpromazine (Wode-Helgodt and Alfredsson, 198 l), but not for haloperidol (Shvarts- burd et al., 1983), or perphenazine (Mazure et al., 1990). The present results suggest no significant effect of age on zotepine kinetics, though this may not be extrapolated to patients aged below 18 years or over 68 years.

The lack of a significant gender difference in zote- pine kinetics has also been shown for the majority

334 K. OTANI ET A L .

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Figure 2. zotepine. BZP = benzodiazepine. The horizontal lines in the figure indicate the mean values of each group

The effect of co-administration of benzodiazepines on the concentration/dose ratios (C/D ratios) of

of antipsychotic drugs (Wode-Helgodt and Alfredsson, 1981; Alfredsson et al., 1984; Eres- hefsky et al., 1985; Mazure et al., 1990).

Disproportionate increases in blood concen- trations with ascending doses have been reported for perphenazine (Bolvig Hansen and Larsen, 1977), and haloperidol (Morselli et al., 1980; Shvartsburd et al., 1983), suggesting dose-depen- dent kinetics of these drugs. In the present study there were no significant differences in the mean CID ratios between 100 mglday and 200 mglday

doses, suggesting no dose-dependent kinetics of zotepine, at least in the dose range used.

Chlorpromazine (Loga et al., 1975; Harman et al., 1980) and flupenthixol (Salem et al., 1982), but not fluphenazine (Harman et al., 1980), are known to induce microsomal enzymes. In the present study, enzyme induction was not measured directly; however, the mean C/D ratios of zotepine in the 24 cases were stable up to 4 weeks after initiation of treatment, suggesting no enzyme-inducing effect of the drug, at least up to 4 weeks.

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STEADY-STATE SERUM KINETICS OF ZOTEPINE

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30 so Age (years )

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Figure 3. The correlation between age and the concentration/dose ratios (C/D ratios) of zotepine

Thus, there is a large inter-individual variation in the steady-state serum kinetics of zotepine. Smoking enhances, while co-administration of ben- zodiazepines may inhibit, the metabolism. Age and gender do not appear to affect the kinetics of the drug. There is no evidence for dose-dependent kine- tics or an enzyme-inducing effect of the drug.

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