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Effect of carbamazepine on the single oral dose pharmacokinetics of perospirone and its active metabolite

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Abstract

Perospirone is a serotonin 5-HT2A and dopamine D2 receptor antagonist which originated in Japan. It has been shown that perospirone is metabolized to ID-15036 mainly by CYP3A4 based on an in vitro study. To investigate the metabolism of perospirone in humans, the authors measured the concentration of perospirone and ID-15036 after a single oral dose of perospirone (8 mg) in 10 healthy male subjects, before and during coadministration of carbamazepine, known as a potent inducer of CYP3A4. Before carbamazepine coadministration, the peak plasma concentrations ± SD of perospirone and ID-15036 were 4.0 ± 4.3 and 11.7 ± 7.1 ng/ml, respectively. During carbamazepine coadministration, the concentration of perospirone was decreased below the detection limit, and that of ID-15036 was 6.0 ± 1.7 ng/ml. The concentrations of perospirone and ID-15036 were influenced significantly by the treatment with carbamazepine, and this was probably attributable to the induction of CYP3A4. This study provided an in vivo evidence of involvement of CYP3A4 in the metabolism of perospirone.

Introduction

Perospirone (PER) is a serotonin 5-HT2A and dopamine D2 receptor antagonist which originated in Japan. This agent has become widely used because of a better side effect profile than conventional antipsychotics. In the clinical situation, the risk of side effects such as extra-pyramidal symptoms (EPS) induced by PER is likely to increase in proportion to the dose. It is believed that EPS is related to some serotonin/dopamine interaction (Casey, 1996). Our previous reports are also supportive to this observation (Takahashi et al., 1998), in which PER predominantly showed a higher 5-HT2A/D2 ratio at lower doses, while the advantage of 5-HT2A receptor occupancy over D2 receptor occupancy was lost at higher doses. Such a tendency is very similar to risperidone (Matsubara et al., 1993), and it has been reported that the incidence of EPS was significantly higher in patients treated with higher doses of risperidone (Marder and Meibach, 1994). On the other hand, 5-HT2A receptor occupancy by ID-15036, a major active metabolite of PER, was predominantly observed even at higher doses. This suggests that PER has a biochemical profile similar to that for clozapine and olanzapine (Takahashi et al., 1998). Consequently, it is assumed that clinical characteristic of ID-15036 is different from that of PER.

In previous case reports, we showed that carbamazepine (CBZ) was effective against perospirone-induced akathisia (Masui et al., 2005). It has been considered that PER is metabolized to ID-15036 mainly by cytochrome P450 (CYP) 3A4 based on an in vitro study (Mizuno et al., 2003). Therefore, when PER is administered with CBZ, well known as a potent inducer of CYP3A4 (Wilkinson, 1996), it is expected that pharmacokinetics of PER can be altered. This pharmacokinetic alteration may be the main mechanism underlying the anti-akathisic effect of CBZ.

Here, the authors investigated the pharmacokinetics of PER at single oral dose under concomitant use of CBZ, and the in vivo effect of altered pharmacokinetics by a measurement of prolactin levels, which is regarded as an indicator of dopamine D2 receptor blockade, in healthy volunteers.

Section snippets

Subjects

The subjects of this study were 10 physically and mentally healthy male volunteers. The mean ± SD (range) of age and body weight were 37.6 ± 8.8 (28–53) years old and 71.6 ± 9.3 (57–86) kg. None had taken any drug or food that affects CYP3A4 activity for at least 4 weeks before introduction of this study. After complete explanation of the study, the written informed consent was obtained from all subjects. The study protocol was approved by the Ethics Committee of Hokkaido University Graduate School

Results

The mean plasma concentrations of PER and ID-15036 before and during CBZ coadministration are shown in Fig. 1. Before CBZ coadministration, the plasma concentration of PER was detectable up to 8 h after dosing. During CBZ coadministration, the plasma concentration of PER decreased under lowest limit of detection at all points of blood sampling in 6 subjects, and the peak plasma PER concentrations in the remaining 4 subjects also decreased (< 1.9 ng/ml. Data not shown.). ID-15036 also decreased

Discussion

In the present study, Cmax, T1/2 and AUC0–∞ of ID-15036 were 3-fold, 1.5-fold and 5-fold higher than those of PER before CBZ coadministration. Similar predominance of ID-15036 over PER was shown in the clinical phase I trial of PER (Inanaga et al., 1997). Based on these results and our previous receptor binding study (Takahashi et al., 1998), ID-15036 is expected to have important roles regarding both antipsychotic effect and amelioration of EPS when PER is administered orally, although

Conclusion

This study showed that CBZ greatly decreased plasma PER concentration, and confirmed the involvement of CYP3A4 in metabolism of PER in human. Although coadministration of CBZ during PER therapy works successfully in some cases, it is possible that decrease in PER concentration may be at risk of aggravation of psychotic symptoms. Therefore, clinicians should pay more attention when PER and CBZ are administered concomitantly.

Acknowledgement

This work was partly supported by grants-in-aid for Scientific Research no. 13670978 (I. Kusumi) from Japanese Ministry of Education, Culture, Sports, Science and Technology.

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