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Perazine elevates clozapine serum levels by inhibiting hepatic metabolism
Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 908–909
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Perazine elevates clozapine serum levels by inhibiting hepatic metabolism 1. Introduction Clozapine, an atypical antipsychotic drug, is a substrate for CYP450 isozymes. Many studies found that CYP1A2 and CYP3A4 are the mainly involved CYP450 isozymes in metabolism of clozapine and recommended monitoring of serum level because of possible drug interactions. Chetty and Murray (2007) referred about possible consistent and predictable interactions between clozapine and potent CYP1A2 inhibitors (i.e. fluvoxamine) or inducers (i.e. cigarette smoke). Perazine is an antipsychotic drug of the group of phenothiazine derivatives. It is a substrate for CYP450 isozymes, in particular CYP3A4 and 2C9 (Strömer et al., 2000). In vitro investigations of Daniel et al., (2001) demonstrated perazine to be a powerful inhibitor of CYP1A2, but to our knowledge, no case reports or clinical trials gave evidence for a clinical importance. 2. Case report “Mrs. L,” a 50-year-old woman, was treated as an inpatient because of a previously diagnosed paranoid schizophrenia (ICD-10 diagnosis) since November 2007. At admission “Mrs. L” received a pharmaceutical treatment including olanzapine (30 mg) and perazine (700 mg), but still showed positive and negative psychotic symptoms. Because of treatment-resistant schizophrenia our intention was to change from polypharmacotherapy (olanzapine and perazine) to a mono-therapy with clozapine. So we tapered olanzapine and started clozapine treatment (defined as day 0 in Fig. 1) increasing the dose according to international guidelines. On day twenty-one (see Fig. 1) “Mrs. L”
received no other drugs than clozapine (250 mg) and perazine (500 mg). At this time serum level of clozapine was 827 mg/l. Unfortunately we did not quantify clozapine serum levels prior to day 15. The interval between clozapine application and blood withdrawal regularly covered 12 h. Six days later, the patient receiving the same dose of clozapine and a reduced dose of perazine (300 mg), clozapine serum level increased to 1234 mg/l. Fig. 1 shows the course of clozapine and perazine dose administered to the patient and the corresponding clozapine serum level. After discontinuation of perazine, we continuously increased the administered clozapine dose and did not observe any further relevant peaks concerning clozapine serum levels (see Fig. 1). 3. Discussion and conclusion Perazine is an old drug, commercially available in few European countries which limits the relevance of this case. Nevertheless to our knowledge, this is the first report of a patient with a significant elevation of clozapine serum levels by concomitant perazine drug therapy. There were no clinical signs for missing compliance such as worsening of symptoms, intake of any other drugs or other clinical conditions that may explain the temporary elevation of clozapine serum levels. The drug was administered under control of psychiatric nurses. We assume that the co-medication with perazine, which has been proposed to be a potent inhibitor of liver enzymes, has lead to the increase of clozapine serum levels. A study investigating the effects of perazine in the rat liver showed that phenothiazine neuroleptics significantly alter the rate of caffein demethylation and hydroxylation which are important pathways for drug elimination, among others via CYP1A2 and CYP3A4 (Daniel et al., 2001). We regard the dramatic increase of clozapine serum level between day 15 and day 25 (see figure) as a result of the additional inhibition of hepatic enzymes (CYP1A2 and/or CYP3A4) due to perazine application. It is surprising that clozapine level increases from 827 mg/l to 1234 mg/l after six days of an approximately stable clozapine dose and a decrease in perazine dose. One possible explanation is that clozapine had not reached steady state at day 15. In addition the persistence of high serum levels of perazine (t1/2= ~35 h) may explain why the inhibitory effects maintained despite the dosage reduction. In the following we continuously increased the clozapine dose (400 mg, day 119) and did not observe further relevant peaks of clozapine serum levels which underlines the potential interaction between perazine and clozapine. It is noteworthy that this patient has not suffered from any sideeffects due to clozapine treatment, even with high clozapine serum levels. Nevertheless, clinicians should be aware of possible drug interaction between clozapine and perazine due to inhibition of hepatic metabolism. Acknowledgments
Fig. 1. The figure suggests that the serum level of clozapine is influenced by parallel treatment with perazine. Day 0 is after cessation of olanzapine and first day of clozapine treatment. 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.04.006
None of the authors has had a financial or personal conflict of interest.
Letter to the Editor (Case report)
References Chetty M, Murray M. CYP-mediated clozapin interactions: how predictable are they? Curr Drug Metab 2007;8(4):307–13. Strömer E, Brockmöller J, Roots I, Schmider J. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Psychopharmacology (Berl.) 2000;151(4):312–20. Daniel WA, Syrek M, Rylko Z, Kot M. Effects of phenothiazine neuroleptics on the rate of caffein demethylation and hydroxylation in the rat liver. Pol J Pharmacol 2001;53(6):615–21.
Gerd Schaller⁎ Andrea Jacobi Andrea Rotter Johannes Kornhuber Thomas Hillemacher1 Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany ⁎Corresponding author. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel.: +49 9131 8544886; fax: +49 9131 8536931. E-mail address: [email protected] (G. Schaller). 23 February 2009
1 "Present address: Clinic for Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany".
909
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Perazine elevates clozapine serum levels by inhibiting hepatic metabolism 1. Introduction Clozapine, an atypical antipsychotic drug, is a substrate for CYP450 isozymes. Many studies found that CYP1A2 and CYP3A4 are the mainly involved CYP450 isozymes in metabolism of clozapine and recommended monitoring of serum level because of possible drug interactions. Chetty and Murray (2007) referred about possible consistent and predictable interactions between clozapine and potent CYP1A2 inhibitors (i.e. fluvoxamine) or inducers (i.e. cigarette smoke). Perazine is an antipsychotic drug of the group of phenothiazine derivatives. It is a substrate for CYP450 isozymes, in particular CYP3A4 and 2C9 (Strömer et al., 2000). In vitro investigations of Daniel et al., (2001) demonstrated perazine to be a powerful inhibitor of CYP1A2, but to our knowledge, no case reports or clinical trials gave evidence for a clinical importance. 2. Case report “Mrs. L,” a 50-year-old woman, was treated as an inpatient because of a previously diagnosed paranoid schizophrenia (ICD-10 diagnosis) since November 2007. At admission “Mrs. L” received a pharmaceutical treatment including olanzapine (30 mg) and perazine (700 mg), but still showed positive and negative psychotic symptoms. Because of treatment-resistant schizophrenia our intention was to change from polypharmacotherapy (olanzapine and perazine) to a mono-therapy with clozapine. So we tapered olanzapine and started clozapine treatment (defined as day 0 in Fig. 1) increasing the dose according to international guidelines. On day twenty-one (see Fig. 1) “Mrs. L”
received no other drugs than clozapine (250 mg) and perazine (500 mg). At this time serum level of clozapine was 827 mg/l. Unfortunately we did not quantify clozapine serum levels prior to day 15. The interval between clozapine application and blood withdrawal regularly covered 12 h. Six days later, the patient receiving the same dose of clozapine and a reduced dose of perazine (300 mg), clozapine serum level increased to 1234 mg/l. Fig. 1 shows the course of clozapine and perazine dose administered to the patient and the corresponding clozapine serum level. After discontinuation of perazine, we continuously increased the administered clozapine dose and did not observe any further relevant peaks concerning clozapine serum levels (see Fig. 1). 3. Discussion and conclusion Perazine is an old drug, commercially available in few European countries which limits the relevance of this case. Nevertheless to our knowledge, this is the first report of a patient with a significant elevation of clozapine serum levels by concomitant perazine drug therapy. There were no clinical signs for missing compliance such as worsening of symptoms, intake of any other drugs or other clinical conditions that may explain the temporary elevation of clozapine serum levels. The drug was administered under control of psychiatric nurses. We assume that the co-medication with perazine, which has been proposed to be a potent inhibitor of liver enzymes, has lead to the increase of clozapine serum levels. A study investigating the effects of perazine in the rat liver showed that phenothiazine neuroleptics significantly alter the rate of caffein demethylation and hydroxylation which are important pathways for drug elimination, among others via CYP1A2 and CYP3A4 (Daniel et al., 2001). We regard the dramatic increase of clozapine serum level between day 15 and day 25 (see figure) as a result of the additional inhibition of hepatic enzymes (CYP1A2 and/or CYP3A4) due to perazine application. It is surprising that clozapine level increases from 827 mg/l to 1234 mg/l after six days of an approximately stable clozapine dose and a decrease in perazine dose. One possible explanation is that clozapine had not reached steady state at day 15. In addition the persistence of high serum levels of perazine (t1/2= ~35 h) may explain why the inhibitory effects maintained despite the dosage reduction. In the following we continuously increased the clozapine dose (400 mg, day 119) and did not observe further relevant peaks of clozapine serum levels which underlines the potential interaction between perazine and clozapine. It is noteworthy that this patient has not suffered from any sideeffects due to clozapine treatment, even with high clozapine serum levels. Nevertheless, clinicians should be aware of possible drug interaction between clozapine and perazine due to inhibition of hepatic metabolism. Acknowledgments
Fig. 1. The figure suggests that the serum level of clozapine is influenced by parallel treatment with perazine. Day 0 is after cessation of olanzapine and first day of clozapine treatment. 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.04.006
None of the authors has had a financial or personal conflict of interest.
Letter to the Editor (Case report)
References Chetty M, Murray M. CYP-mediated clozapin interactions: how predictable are they? Curr Drug Metab 2007;8(4):307–13. Strömer E, Brockmöller J, Roots I, Schmider J. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Psychopharmacology (Berl.) 2000;151(4):312–20. Daniel WA, Syrek M, Rylko Z, Kot M. Effects of phenothiazine neuroleptics on the rate of caffein demethylation and hydroxylation in the rat liver. Pol J Pharmacol 2001;53(6):615–21.
Gerd Schaller⁎ Andrea Jacobi Andrea Rotter Johannes Kornhuber Thomas Hillemacher1 Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany ⁎Corresponding author. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel.: +49 9131 8544886; fax: +49 9131 8536931. E-mail address: [email protected] (G. Schaller). 23 February 2009
1 "Present address: Clinic for Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany".
909