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Effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs
International Congress Series 1244 (2002) 21 – 31
Effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs Norio Yasui-Furukori a,*, Tomonori Tateishi a, Tsuyoshi Kondo b, Kazuo Mihara b, Akihito Suzuki b, Shingo Ono b, Sunao Kaneko b a
Department of Clinical Pharmacology, Hirosaki University School of Medicine, 5 Zaifu, Hirosaki 036-8562, Japan b Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
Abstract Most of neuroleptics has been reported as a substrate of not only cytochrome P450 (CYP) 2D6, but also CYP3A4. Thus, the effect of CYP2D6 genotype on pharmacokinetic interactions with a CYP3A4 inhibitor or inducer was examined in Japanese patients with psychiatric disorders who were treated with neuroleptics. Thirteen schizophrenic patients treated with haloperidol at 12 or 24 mg/day (Group 1) and and another nine treated with risperidone at 6 mg/day (Group 2) participated in the studies. Itraconazole (CYP3A4 inhibitor) and carbamazepine (CYP3A4 inducer) were coadministered in Groups 1 and 2, respectively. Blood samplings were performed before and after the coadministration, and plasma drug concentrations were determined using HPLC. CYP2D6 genotypes were identified using PCR method. Itraconazole and carbamazepine significantly altered plasma drug concentrations in Groups 1 and 2, respectively. There was no difference in the inhibition degree by itraconazole between different CYP2D6 genotypes in Group 1. In contrast, significant difference was found in the induction degree by carbamazepine between different CYP2D6 genotypes in Group 2. The present studies, thus, show that CYP2D6 genotype has an impact on drug interaction with risperidone, but not haloperidol. These findings suggest that CYP2D6 predominantly involved in risperidone metabolism, compared with haloperidol. D 2002 Elsevier Science B.V. All rights reserved. Keywords: CYP2D6; Haloperidol; Riseridone; CYP3A4; Drug interaction
1. Introduction Most neuroleptics have been reported as substrates of cytochrome P450 (CYP) 2D6 including haloperidol [1], risperidone [2], thioridazine [3], perphenazine [1] and zuclo*
Corresponding author. Tel./fax: +81-172-39-5352. E-mail address: [email protected] (N. Yasui-Furukori).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 4 5 3 - 3
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penthixol [1]. These drugs have potential risk of drug – drug interaction with CYP2D6 inhibitors such as quinidine [4], fluoxetine [5], paroxetine [5] and levomepromazine [6]. On the other hand, recent in vitro studies with human liver microsome or cell line microsome have suggested that CYP3A4 is also a major enzyme catalyzing the metabolism of neuroleptics that had been known as substrates of CYP2D6. Several studies have consistently demonstrated the involvement of only CYP3A4 in N-dealkylation of haloperidol [7 –9] as well as dehydration to a pyridinium metabolite [8 – 11]. Fang et al. [12] have shown that not only CYP2D6 but also CYP3A4 is a major catalytic enzyme in the 9-hydroxylation of risperidone using human liver microsome and cDNA recombinant microsome, although we have confirmed that CYP2D6 is more predominant than CYP3A4 at low concentrations using the same method [13]. Our previous report has shown that the effect of thioridazine, a CYP2D6 inhibitor in poor metabolizer (PM) of debrisoquine, is very small because they do not have any activity of CYP2D6 [14]. Consequently, we can easily predict the degree of change in drug interaction through only CYP2D6 when CYP2D6 activity in patient has been already proven using CYP2D6 phenotype or CYP2D6 genotype. Many drugs have been turned out to alter the CYP3A4 activity; antifungal agents and macrolide antibiotics can inhibit CYP3A4, and rifampicine and antiepileptic drugs can induce the activity [15]. It is known that CYP2D6 is high affinity and low capacity, while CYP3A4 is low affinity and high capacity. Consequently, it appears that CYP3A4 might play an important role in subjects with low activity of CYP2D6. It is also supposed that CYP2D6 phenotype or CYP2D6 genotype can be a useful marker when CYP3A4 activity is affected in substrates of both CYP2D6 and CYP3A4. To test our hypothesis, the effect of CYP2D6 genotype on pharmacokinetic interactions with a CYP3A4 inhibitor, itraconazole, or a CYP3A4 inducer, carbamazepine, was examined in Japanese patients with psychiatric disorders who were treated with neuroleptics, haloperidol and risperidone.
2. Methods Two studies were separately conducted to examine the effects effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs. The protocols of both studies were approved by the ethics committee of Hirosaki University Hospital, and all subjects in both studies gave their written informed consent before the studies. 2.1. Study 1 2.1.1. Subjects The subjects of Study 1 were 13 physically healthy Japanese inpatients (3 men, 10 women), who fulfilled the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. The mean F S.D. of age, body weight and duration of illness were 47 F 9 years, 58 F 8 kg and 211 F 123 months, respectively.
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2.1.2. Protocol Eleven patients were treated with haloperidol 6 mg twice a day (8 a.m. and 8 p.m.) and two patients were given 12 mg twice a day for 2 – 36 weeks. The elimination half-lives of haloperidol and reduced haloperidol were reported to be 22– 34 and 20 –29 h, respectively [16]. Therefore, plasma concentrations of these compounds already reached steady state in all of the subjects before initiating the study. No other drugs were coadministered except flunitrazepam 2 –6 mg/day in eight patients, biperiden 6 mg/day in all patients and sennoside 12– 36 mg/day in eight cases. The doses of these drugs were fixed throughout the study period. The oral dose of itraconazole 200 mg once a day (8 a.m.) was co-administered to each patient. Blood samples (20 ml) were drawn at 8 a.m. before the morning dose, just before and 1 week after itraconazole co-administration and 1 week after itraconazole discontinuation. 2.2. Study 2 2.2.1. Subjects The subjects were nine schizophrenic inpatients (all of them females), who fulfilled the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. The mean F S.D. of age, body weight and duration of illness were 46 F 13 years, 62 F 8 kg and 213 F 115 months, respectively. 2.2.2. Protocol Before carbamazepine coadministration, the subjects had received risperidone 6 mg twice a day (8 a.m. and 8 p.m.) for 2– 68 weeks. The elimination half-lives of risperidone and 9-hydroxyrisperidone were reported to be 3 –20 and 20 –29 h, respectively [3]. Therefore, plasma concentrations of these compounds already reached steady state in all of the subjects before initiating the study. The drugs coadministered were flunitrazepam 4 – 10 mg/day in all cases, biperiden 4– 6 mg/day in five cases, sennoside 12– 60 mg/day in six cases, diazepam 6 –30 mg/day in three cases, trihexyphenidyl 4 mg/day in one case, lorazepam 3 mg/day in one case and triazolam 0.75 mg/day in one case. The doses of these coadministered drugs were fixed throughout the study period. Carbamazepine 200 mg twice a day (8 a.m. and 8 p.m.) was coadministered to all subjects for at least 1 week and was thereafter withdrawn. Carbamazepine was reintroduced to only a few cases showing some improvement during the 1-week carbamazepine coadministration. Blood samplings were performed before and during carbamazepine coadministration, and 1 week after its discontinuation just before the morning dose. 2.2.3. Assays for haloperidol and risperidone and their metabolites The plasma concentrations of haloperidol and reduced haloperidol were determined in duplicate with use of high-performance liquid chromatography as described by Hikida et al. [17]. The lowest limits of quantification were 0.3 ng/ml, and the values of the interassay coefficient of variation were less than 5% at the concentrations of 1.1 ng/ml for both compounds.
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Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography – mass spectrometry – mass spectrometry (LC – MS– MS) method, the detail of which will be submitted elsewhere in the near future. Extraction procedure was as follows: to 200 Al of plasma sample was added 200 Al of 0.1 M phosphate buffer (pH 7), 50 Al of internal standard solution (R068808: Jansen Research Foundation) and 100 Al of methanol. Thereafter, 400 Al of 0.1 M Borax was added. The mixture is vortexed and poured over an Extrelut NT 1 (Merck) column, which is eluted with 7 ml of ethyl acetate. The eluate was evaporated under a nitrogen stream at 65 jC, and was redissolved in 100 Al of methanol which is again evaporated under a nitrogen stream at 65 jC. The residues were redissolved in 200 Al of acetonitrile/0.01 M ammonium acetate (50/50, pH 9.0), and 5 Al were injected onto the LC – MS– MS system. The system consisted of API 3000 (Sciex) and a column (Hypersil BDS C18 100 4.6, 3 Am). The mobile phase was gradient ammonium acetate (0.01 M, pH 9.0)-acetonitrile. Among the fragment ions of the compounds, the mass-to-charge ratio (m/z) 207.0 for risperidone, m/z 191.0 for 9hydroxyrisperidone and m/z 201.0 for the internal standard were selected for ion monitoring. The lower limit of detection was 0.1 ng/ml, and the values of the interassay coefficient of variation were less than 5% at all the concentrations of calibration curves for risperidone and 9-hydroxyrisperidone. 2.2.4. Analysis for CYP2D6 genotypes For the determination of CYP2D6 genotype, DNA was isolated from peripheral leukocytes by a guanidium isothiocyanate method. The CYP2D6*1 (*1), CYP2D6*3 and CYP2D6*4 alleles were identified by allele specific PCR analysis according to Heim and Meyer [18]. A long-PCR analysis was used to detect the CYP2D6 *5 ( *5) allele [19]. The CYP2D6*10 (*10) allele was identified as the 188C-T mutation using a two-step PCR analysis as described by Johansson et al. [20]. 2.2.5. Statistical analyses Friedman rank test followed by Tukey test as used for the comparision of the plasma drug concentrations among three phases, i.e., before and during carbamazepine treatment and after its discontinuation and for the comparison of plasma drug concentrations and change in drug concentrations among different CYP2D6 genotypes. A p value of 0.05 or less was regarded as significant. SPSS 7.5.1 for Windows SPSS Japan, Tokyo, was used for these statistical analyses.
3. Results 3.1. Study 1 The mean plasma concentrations of both haloperidol and reduced haloperidol during itraconazole coadministration were significantly ( p < 0.01) higher than those measured before itraconazole coadministration or 1 week after its discontinuation (Fig. 1). Individual monitoring also showed the elevated plasma concentrations of both haloperidol and reduced haloperidol during itraconazole treatment in all patients (Fig. 1). However, the
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Fig. 1. Effect of itraconazole co-administration on the plasma concentrations of haloperidol and reduced haloperidol.
concentration ratio of reduced haloperidol to haloperidol during the study were unchanged. The dose of haloperidol did not affect the ratio of increase in plasma concentrations of haloperidol and reduced haloperidol during itraconazole treatment. The CYP2D6 genotype were identified as follows: homozygous for *1/ *1 for four patients, *5/ *5 in one and *10/ *10 in one; and heterozygous for *1/ *5 in one patient, *1/ *10 in five and *5/ *10 in one. The patients were divided into three groups according to the number of mutated alleles, i.e., no (N = 4), one (N = 6) and two mutated alleles (N = 3). Pretreatment of plasma concentrations of haloperidol or deduced haloperidol and the ratio of increase in the plasma concentrations of both compounds during itraconzole treatment were not significantly different among the three groups (Fig. 2, left hand). There were no differences in inhibition rate of haloperidol (Fig. 2, middle hand) or reduced haloperidol (Fig. 2, right hand) by itraconazole among CYP2D6 genotype groups. 3.2. Study 2 Plasma concentrations of risperidone and 9-hydroxyrisperidone during carbamazepine coadministration (1.9 F 3.1 and 18.8 F 4.3 ng/ml) were significantly ( p < 0.05 and p < 0.01) lower than those before carbamazepine coadministration (4.6 F 8.3 and 32.8 F 8.6 ng/ml) (Fig. 3). The concentration of 9-hydroxyrisperidone during carbamazepine coadministration (18.8 F 4.3 ng/ml) was also significantly ( p < 0.05) lower than that after its discontinuation (32.0 F 8.2 ng/ml) (Fig. 3).
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Fig. 2. Effect of CYP2D6 genotype on the steady-state plasma haloperidol concentration per dose (left hand) and inhibition rates for haloperidol (middle hand) and reduced haloperidol (right hand). The solid circle indicates the patients with homozygous alleles for CYP2D6*5, meaning no functional CYP2D6 gene.
Fig. 3. Effect of carbamazepine co-administration on the plasma concentrations of risperidone, 9-hydroxyrisperidone and active moiety. Double circles indicate the values in patient with two mutated alleles (*5/*10) for CYP2D6.
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Fig. 4. Effect of CYP2D6 genotype on the ratios of risperidone/9-hydroxyrisperidone (left hand), the changes in risperidone concentrations before and after carbamazepine co-administration (middle hand) and the their induction rates (percent of control) (right hand).
Three CYP2D6 genotypes were identified in the patients; six homozygotes of the *1 allele, two heterozygotes of the *1 and *10 alleles and one heterozygote of *5 and *10 alleles. The heterozygote of the *5 and *10 alleles showed the highest risperidone/9hydroxyrisperidone ratio (0.58), intermediate values (0.11 and 0.17) in the two heterozygotes of the *1 and *10 alleles, and much lower values (mean F S.D.: 0.04 F 0.01) in the six homozygotes of the *1 allele (Fig. 4, left hand). Similar figure was observed in the changes in risperidone concentrations before and after carbamazepine coadministration among three CYP2D6 genotypes (Fig. 4, middle hand). Fig. 4 (right hand) also demonstrates induction rate in risperidone concentration after carbamazepine coadministration (the ratios of risperidone concentration after co-administration/before co-administration) among three CYP2D6 genotypes. Large induction rate (about 50%) was found in patients with mutated allele(s), whereas there was variability in induction rate (50% to 100%) in patients without mutated allele.
4. Discussion Itraconazole, a potent inhibitor of CYP3A4, significantly increased the mean steadystate plasma concentration of haloperidol. This may be explained by the inhibitory effect of itraconazole on the metabolism of haloperidol. Our study supports previous in vitro studies suggesting involvement of CYP3A4 in haloperidol metabolism. However, change
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in the steady-state plasma concentration of haloperidol did not have a strong impact compared with the dramatic changes in pharmacokinetic of midazolam [21] and triazolam [22], both of which are specific substrates of CYP3A4 [14], although a dose schedule of itraconazole treatment similar to that used in our study was adopted in these studies. It is, therefore, reasonable to conclude that CYP3A4 catalyzes only a part of the metabolism of haloperidol. Involvement of CYP2D6 in the metabolism of haloperidol has been established by both in vitro [9] and in vivo studies [23 –25]. However, we could not find any difference in the pretreatment plasma concentrations of haloperidol and reduced haloperidol among the different CYP2D6 genotype groups. Thus, it may be suggested that CYP2D6 activity is not a determinant factor for whole metabolism of haloperidol because alternative enzymes other than CYP2D6, e.g., glucronosyltransferase [26], carbonyl reductase [27], CYP3A4 and possibly CYP1A2 [28] also may play important roles in the metabolism of haloperidol. The inhibitory effects of itraconazole on haloperidol metabolism are independent of CYP2D6 activity because the increase in ratio of haloperidol concentrations during itraconazole treatment in patients with one or two mutated alleles were almost similar to those in patients with no mutated allele. These findings suggest that CYP2D6 genotype is unlikely to predict impact on drug interaction between haloperidol and CYP3A4 inhibitors. The 9-hydroxylation is the initial major metabolic pathway of risperidone [29]. The metabolite, 9-hydroxyrisperidone is pharmacologically active and plays an important role in pharmacological actions of risperidone [2]. Huang et al. [2] studied the disposition of risperidone and 9-hydroxyrisperidone after a single oral dose of risperidone in a panel of extensive and poor metabolizers of CYP2D6. They clearly showed decreased 9-hydroxylation of risperidone in poor metabolizers of CYP2D6. Also, genotype analysis for CYP2D6 including poor metabolizers as the subjects revealed that the ratio of risperidone/ 9-hydroxyrisperidone was strongly dependent on CYP2D6 genotypes [30]. The present results again showed that CYP2D6 genotypes greatly affected the ratios of risperidone/9hydroxyrisperidone even among extensive metabolizers (Fig. 4, left hand). Although previous preliminary in vitro study using human liver microsomes [12] showed that the formation of 9-hydroxyrisperidone was catalyzed not only by CYP2D6 but also by CYP3A4, it is most likely that 9-hydroxylation, the major metabolic pathway of risperidone, is mainly dependent on CYP2D6 activity in clinical situations. This has been confirmed by our recent in vitro study using low substrate concentrations [13]. In the present study 2, significant intraindividual changes were observed in plasma concentrations of both risperidone and 9-hydroxyrisperidone during carbamazepine coadministration. This is in line with the previous report showing that plasma concentrations of risperidone and 9-hydroxyrisperidone in subjects receiving combination therapy with risperidone and carbamazepine are lower than those receiving risperidone alone [31]. It is likely that isozyme(s), e.g., CYP3A4, induced by carbamazepine is (are) involved in the metabolism of risperidone and 9-hydroxyrisperidone. On the other hand, the concentration ratios of risperidone/9-hydroxyrisperidone remained unchanged irrespective of coadministration or withdrawal of carbamazepine. These findings are because of the fact that 9-hydroxylation of risperidone is in principle CYP2D6-dependent and is scarcely affected by increased CYP3A4 activity during carbamazepine coadministration.
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The decreased risperidone concentrations by carbamazepine coadministration are unlikely due to enhanced 9-hydroxylation of risperidone since the concentrations of 9hydroxyrisperidone also significantly decreased in the present study 2. It is rather suggested that carbamazepine enhances other metabolic pathways of risperidone e.g., alicyclic dehydroxylation and/or oxdative N-dealkylation, probably via induction of CYP3A4. Furthermore, the changes in risperidone concentrations before and after carbamazepine coadministration were also closely associated with CYP2D6 genotypes (Fig. 4, middle hand). Provided that the ratio of risperidone/9-hydroxyrisperidone is an index of CYP2D6 activity, this finding implies that carbamazepine coadministration has a stronger impact on risperidone metabolism in subjects with less activity of CYP2D6. This is supported by a case report in which coadministration of carbamzepine in a poor CYP2D6 metabolizer resulted in a decrease in plasma concentration of risperidone and 9-hydroxyrisperidone [32]. In such cases, the metabolism catalyzed by carbamazepine inducible enzyme(s) other than CYP2D6 might have been originally an important compensation for limited capacity of CYP2D6-dependent 9-hydroxylation of risperidone. In conclusion, the present studies show that CYP2D6 genotype has an impact on drug interaction with risperidone, but not haloperidol. These findings suggest that CYP2D6 predominantly involved in risperidone metabolism, compared with haloperidol. Acknowledgements The authors are grateful to Yoshimasa Inoue (Pharmaceutical Research Division, Mitsubishi Welfarma) and Ronald de Vries (Department of Pharmacokinetics, RV, Janssen Research Foundation) for providing HPLC or LC – MS –MS technical support. References [1] L. Bertilsson, M.L. Dahl, B. Ekqvist, A. Llerena, Disposition of the neuroleptics perphenazine, zuclopenthixol, and haloperidol cosegregates with polymorphic debrisoquine hydroxylation, Psychopharmacol. Ser. 10 (1993) 230 – 237. [2] M.L. Huang, A. Van Peer, R. Woestenborghs, R. De Coster, J. Heykants, A.A. Jansen, Z. Zylicz, H.W. Visscher, J.H. Jonkman, Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects, Clin. Pharmacol. Ther. 54 (3) (1993) 257 – 268. [3] A. Llerena, R. Berecz, A. de la Rubia, M.J. Norberto, J. Benitez, Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity, Ther. Drug Monit. 22 (4) (2000) 397 – 401. [4] R.A. Branch, A. Adedoyin, R.F. Frye, J.W. Wilson, M. Romkes, In vivo modulation of CYP enzymes by quinidine and rifampin, Clin. Pharmacol. Ther. 68 (4) (2000) 401 – 411. [5] U. Jeppesen, L.F. Gram, K. Vistisen, S. Loft, H.E. Poulsen, K. Brosen, Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine, Eur. J. Clin. Pharmacol. 51 (1) (1996) 73 – 77. [6] J. Kallio, R. Huupponen, M. Seppala, E. Sako, E. Iisalo, The effects of beta-adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine, Br. J. Clin. Pharmacol. 30 (4) (1990) 638 – 643. [7] L.P. Pan, P. Wijnant, C. De Vriendt, M.T. Rosseel, F.M. Belpaire, Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol, Br. J. Clin. Pharmacol. 44 (6) (1997) 557 – 564. [8] J. Fang, G.B. Baker, P.H. Silverstone, R.T. Coutts, Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol, Cell. Mol. Neurobiol. 17 (2) (1997) 227 – 233.
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Effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs Norio Yasui-Furukori a,*, Tomonori Tateishi a, Tsuyoshi Kondo b, Kazuo Mihara b, Akihito Suzuki b, Shingo Ono b, Sunao Kaneko b a
Department of Clinical Pharmacology, Hirosaki University School of Medicine, 5 Zaifu, Hirosaki 036-8562, Japan b Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
Abstract Most of neuroleptics has been reported as a substrate of not only cytochrome P450 (CYP) 2D6, but also CYP3A4. Thus, the effect of CYP2D6 genotype on pharmacokinetic interactions with a CYP3A4 inhibitor or inducer was examined in Japanese patients with psychiatric disorders who were treated with neuroleptics. Thirteen schizophrenic patients treated with haloperidol at 12 or 24 mg/day (Group 1) and and another nine treated with risperidone at 6 mg/day (Group 2) participated in the studies. Itraconazole (CYP3A4 inhibitor) and carbamazepine (CYP3A4 inducer) were coadministered in Groups 1 and 2, respectively. Blood samplings were performed before and after the coadministration, and plasma drug concentrations were determined using HPLC. CYP2D6 genotypes were identified using PCR method. Itraconazole and carbamazepine significantly altered plasma drug concentrations in Groups 1 and 2, respectively. There was no difference in the inhibition degree by itraconazole between different CYP2D6 genotypes in Group 1. In contrast, significant difference was found in the induction degree by carbamazepine between different CYP2D6 genotypes in Group 2. The present studies, thus, show that CYP2D6 genotype has an impact on drug interaction with risperidone, but not haloperidol. These findings suggest that CYP2D6 predominantly involved in risperidone metabolism, compared with haloperidol. D 2002 Elsevier Science B.V. All rights reserved. Keywords: CYP2D6; Haloperidol; Riseridone; CYP3A4; Drug interaction
1. Introduction Most neuroleptics have been reported as substrates of cytochrome P450 (CYP) 2D6 including haloperidol [1], risperidone [2], thioridazine [3], perphenazine [1] and zuclo*
Corresponding author. Tel./fax: +81-172-39-5352. E-mail address: [email protected] (N. Yasui-Furukori).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 4 5 3 - 3
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penthixol [1]. These drugs have potential risk of drug – drug interaction with CYP2D6 inhibitors such as quinidine [4], fluoxetine [5], paroxetine [5] and levomepromazine [6]. On the other hand, recent in vitro studies with human liver microsome or cell line microsome have suggested that CYP3A4 is also a major enzyme catalyzing the metabolism of neuroleptics that had been known as substrates of CYP2D6. Several studies have consistently demonstrated the involvement of only CYP3A4 in N-dealkylation of haloperidol [7 –9] as well as dehydration to a pyridinium metabolite [8 – 11]. Fang et al. [12] have shown that not only CYP2D6 but also CYP3A4 is a major catalytic enzyme in the 9-hydroxylation of risperidone using human liver microsome and cDNA recombinant microsome, although we have confirmed that CYP2D6 is more predominant than CYP3A4 at low concentrations using the same method [13]. Our previous report has shown that the effect of thioridazine, a CYP2D6 inhibitor in poor metabolizer (PM) of debrisoquine, is very small because they do not have any activity of CYP2D6 [14]. Consequently, we can easily predict the degree of change in drug interaction through only CYP2D6 when CYP2D6 activity in patient has been already proven using CYP2D6 phenotype or CYP2D6 genotype. Many drugs have been turned out to alter the CYP3A4 activity; antifungal agents and macrolide antibiotics can inhibit CYP3A4, and rifampicine and antiepileptic drugs can induce the activity [15]. It is known that CYP2D6 is high affinity and low capacity, while CYP3A4 is low affinity and high capacity. Consequently, it appears that CYP3A4 might play an important role in subjects with low activity of CYP2D6. It is also supposed that CYP2D6 phenotype or CYP2D6 genotype can be a useful marker when CYP3A4 activity is affected in substrates of both CYP2D6 and CYP3A4. To test our hypothesis, the effect of CYP2D6 genotype on pharmacokinetic interactions with a CYP3A4 inhibitor, itraconazole, or a CYP3A4 inducer, carbamazepine, was examined in Japanese patients with psychiatric disorders who were treated with neuroleptics, haloperidol and risperidone.
2. Methods Two studies were separately conducted to examine the effects effect of CYP2D6 genotype on pharmacokinetic interactions with psychotropic drugs. The protocols of both studies were approved by the ethics committee of Hirosaki University Hospital, and all subjects in both studies gave their written informed consent before the studies. 2.1. Study 1 2.1.1. Subjects The subjects of Study 1 were 13 physically healthy Japanese inpatients (3 men, 10 women), who fulfilled the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. The mean F S.D. of age, body weight and duration of illness were 47 F 9 years, 58 F 8 kg and 211 F 123 months, respectively.
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2.1.2. Protocol Eleven patients were treated with haloperidol 6 mg twice a day (8 a.m. and 8 p.m.) and two patients were given 12 mg twice a day for 2 – 36 weeks. The elimination half-lives of haloperidol and reduced haloperidol were reported to be 22– 34 and 20 –29 h, respectively [16]. Therefore, plasma concentrations of these compounds already reached steady state in all of the subjects before initiating the study. No other drugs were coadministered except flunitrazepam 2 –6 mg/day in eight patients, biperiden 6 mg/day in all patients and sennoside 12– 36 mg/day in eight cases. The doses of these drugs were fixed throughout the study period. The oral dose of itraconazole 200 mg once a day (8 a.m.) was co-administered to each patient. Blood samples (20 ml) were drawn at 8 a.m. before the morning dose, just before and 1 week after itraconazole co-administration and 1 week after itraconazole discontinuation. 2.2. Study 2 2.2.1. Subjects The subjects were nine schizophrenic inpatients (all of them females), who fulfilled the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. The mean F S.D. of age, body weight and duration of illness were 46 F 13 years, 62 F 8 kg and 213 F 115 months, respectively. 2.2.2. Protocol Before carbamazepine coadministration, the subjects had received risperidone 6 mg twice a day (8 a.m. and 8 p.m.) for 2– 68 weeks. The elimination half-lives of risperidone and 9-hydroxyrisperidone were reported to be 3 –20 and 20 –29 h, respectively [3]. Therefore, plasma concentrations of these compounds already reached steady state in all of the subjects before initiating the study. The drugs coadministered were flunitrazepam 4 – 10 mg/day in all cases, biperiden 4– 6 mg/day in five cases, sennoside 12– 60 mg/day in six cases, diazepam 6 –30 mg/day in three cases, trihexyphenidyl 4 mg/day in one case, lorazepam 3 mg/day in one case and triazolam 0.75 mg/day in one case. The doses of these coadministered drugs were fixed throughout the study period. Carbamazepine 200 mg twice a day (8 a.m. and 8 p.m.) was coadministered to all subjects for at least 1 week and was thereafter withdrawn. Carbamazepine was reintroduced to only a few cases showing some improvement during the 1-week carbamazepine coadministration. Blood samplings were performed before and during carbamazepine coadministration, and 1 week after its discontinuation just before the morning dose. 2.2.3. Assays for haloperidol and risperidone and their metabolites The plasma concentrations of haloperidol and reduced haloperidol were determined in duplicate with use of high-performance liquid chromatography as described by Hikida et al. [17]. The lowest limits of quantification were 0.3 ng/ml, and the values of the interassay coefficient of variation were less than 5% at the concentrations of 1.1 ng/ml for both compounds.
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Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography – mass spectrometry – mass spectrometry (LC – MS– MS) method, the detail of which will be submitted elsewhere in the near future. Extraction procedure was as follows: to 200 Al of plasma sample was added 200 Al of 0.1 M phosphate buffer (pH 7), 50 Al of internal standard solution (R068808: Jansen Research Foundation) and 100 Al of methanol. Thereafter, 400 Al of 0.1 M Borax was added. The mixture is vortexed and poured over an Extrelut NT 1 (Merck) column, which is eluted with 7 ml of ethyl acetate. The eluate was evaporated under a nitrogen stream at 65 jC, and was redissolved in 100 Al of methanol which is again evaporated under a nitrogen stream at 65 jC. The residues were redissolved in 200 Al of acetonitrile/0.01 M ammonium acetate (50/50, pH 9.0), and 5 Al were injected onto the LC – MS– MS system. The system consisted of API 3000 (Sciex) and a column (Hypersil BDS C18 100 4.6, 3 Am). The mobile phase was gradient ammonium acetate (0.01 M, pH 9.0)-acetonitrile. Among the fragment ions of the compounds, the mass-to-charge ratio (m/z) 207.0 for risperidone, m/z 191.0 for 9hydroxyrisperidone and m/z 201.0 for the internal standard were selected for ion monitoring. The lower limit of detection was 0.1 ng/ml, and the values of the interassay coefficient of variation were less than 5% at all the concentrations of calibration curves for risperidone and 9-hydroxyrisperidone. 2.2.4. Analysis for CYP2D6 genotypes For the determination of CYP2D6 genotype, DNA was isolated from peripheral leukocytes by a guanidium isothiocyanate method. The CYP2D6*1 (*1), CYP2D6*3 and CYP2D6*4 alleles were identified by allele specific PCR analysis according to Heim and Meyer [18]. A long-PCR analysis was used to detect the CYP2D6 *5 ( *5) allele [19]. The CYP2D6*10 (*10) allele was identified as the 188C-T mutation using a two-step PCR analysis as described by Johansson et al. [20]. 2.2.5. Statistical analyses Friedman rank test followed by Tukey test as used for the comparision of the plasma drug concentrations among three phases, i.e., before and during carbamazepine treatment and after its discontinuation and for the comparison of plasma drug concentrations and change in drug concentrations among different CYP2D6 genotypes. A p value of 0.05 or less was regarded as significant. SPSS 7.5.1 for Windows SPSS Japan, Tokyo, was used for these statistical analyses.
3. Results 3.1. Study 1 The mean plasma concentrations of both haloperidol and reduced haloperidol during itraconazole coadministration were significantly ( p < 0.01) higher than those measured before itraconazole coadministration or 1 week after its discontinuation (Fig. 1). Individual monitoring also showed the elevated plasma concentrations of both haloperidol and reduced haloperidol during itraconazole treatment in all patients (Fig. 1). However, the
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Fig. 1. Effect of itraconazole co-administration on the plasma concentrations of haloperidol and reduced haloperidol.
concentration ratio of reduced haloperidol to haloperidol during the study were unchanged. The dose of haloperidol did not affect the ratio of increase in plasma concentrations of haloperidol and reduced haloperidol during itraconazole treatment. The CYP2D6 genotype were identified as follows: homozygous for *1/ *1 for four patients, *5/ *5 in one and *10/ *10 in one; and heterozygous for *1/ *5 in one patient, *1/ *10 in five and *5/ *10 in one. The patients were divided into three groups according to the number of mutated alleles, i.e., no (N = 4), one (N = 6) and two mutated alleles (N = 3). Pretreatment of plasma concentrations of haloperidol or deduced haloperidol and the ratio of increase in the plasma concentrations of both compounds during itraconzole treatment were not significantly different among the three groups (Fig. 2, left hand). There were no differences in inhibition rate of haloperidol (Fig. 2, middle hand) or reduced haloperidol (Fig. 2, right hand) by itraconazole among CYP2D6 genotype groups. 3.2. Study 2 Plasma concentrations of risperidone and 9-hydroxyrisperidone during carbamazepine coadministration (1.9 F 3.1 and 18.8 F 4.3 ng/ml) were significantly ( p < 0.05 and p < 0.01) lower than those before carbamazepine coadministration (4.6 F 8.3 and 32.8 F 8.6 ng/ml) (Fig. 3). The concentration of 9-hydroxyrisperidone during carbamazepine coadministration (18.8 F 4.3 ng/ml) was also significantly ( p < 0.05) lower than that after its discontinuation (32.0 F 8.2 ng/ml) (Fig. 3).
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Fig. 2. Effect of CYP2D6 genotype on the steady-state plasma haloperidol concentration per dose (left hand) and inhibition rates for haloperidol (middle hand) and reduced haloperidol (right hand). The solid circle indicates the patients with homozygous alleles for CYP2D6*5, meaning no functional CYP2D6 gene.
Fig. 3. Effect of carbamazepine co-administration on the plasma concentrations of risperidone, 9-hydroxyrisperidone and active moiety. Double circles indicate the values in patient with two mutated alleles (*5/*10) for CYP2D6.
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Fig. 4. Effect of CYP2D6 genotype on the ratios of risperidone/9-hydroxyrisperidone (left hand), the changes in risperidone concentrations before and after carbamazepine co-administration (middle hand) and the their induction rates (percent of control) (right hand).
Three CYP2D6 genotypes were identified in the patients; six homozygotes of the *1 allele, two heterozygotes of the *1 and *10 alleles and one heterozygote of *5 and *10 alleles. The heterozygote of the *5 and *10 alleles showed the highest risperidone/9hydroxyrisperidone ratio (0.58), intermediate values (0.11 and 0.17) in the two heterozygotes of the *1 and *10 alleles, and much lower values (mean F S.D.: 0.04 F 0.01) in the six homozygotes of the *1 allele (Fig. 4, left hand). Similar figure was observed in the changes in risperidone concentrations before and after carbamazepine coadministration among three CYP2D6 genotypes (Fig. 4, middle hand). Fig. 4 (right hand) also demonstrates induction rate in risperidone concentration after carbamazepine coadministration (the ratios of risperidone concentration after co-administration/before co-administration) among three CYP2D6 genotypes. Large induction rate (about 50%) was found in patients with mutated allele(s), whereas there was variability in induction rate (50% to 100%) in patients without mutated allele.
4. Discussion Itraconazole, a potent inhibitor of CYP3A4, significantly increased the mean steadystate plasma concentration of haloperidol. This may be explained by the inhibitory effect of itraconazole on the metabolism of haloperidol. Our study supports previous in vitro studies suggesting involvement of CYP3A4 in haloperidol metabolism. However, change
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in the steady-state plasma concentration of haloperidol did not have a strong impact compared with the dramatic changes in pharmacokinetic of midazolam [21] and triazolam [22], both of which are specific substrates of CYP3A4 [14], although a dose schedule of itraconazole treatment similar to that used in our study was adopted in these studies. It is, therefore, reasonable to conclude that CYP3A4 catalyzes only a part of the metabolism of haloperidol. Involvement of CYP2D6 in the metabolism of haloperidol has been established by both in vitro [9] and in vivo studies [23 –25]. However, we could not find any difference in the pretreatment plasma concentrations of haloperidol and reduced haloperidol among the different CYP2D6 genotype groups. Thus, it may be suggested that CYP2D6 activity is not a determinant factor for whole metabolism of haloperidol because alternative enzymes other than CYP2D6, e.g., glucronosyltransferase [26], carbonyl reductase [27], CYP3A4 and possibly CYP1A2 [28] also may play important roles in the metabolism of haloperidol. The inhibitory effects of itraconazole on haloperidol metabolism are independent of CYP2D6 activity because the increase in ratio of haloperidol concentrations during itraconazole treatment in patients with one or two mutated alleles were almost similar to those in patients with no mutated allele. These findings suggest that CYP2D6 genotype is unlikely to predict impact on drug interaction between haloperidol and CYP3A4 inhibitors. The 9-hydroxylation is the initial major metabolic pathway of risperidone [29]. The metabolite, 9-hydroxyrisperidone is pharmacologically active and plays an important role in pharmacological actions of risperidone [2]. Huang et al. [2] studied the disposition of risperidone and 9-hydroxyrisperidone after a single oral dose of risperidone in a panel of extensive and poor metabolizers of CYP2D6. They clearly showed decreased 9-hydroxylation of risperidone in poor metabolizers of CYP2D6. Also, genotype analysis for CYP2D6 including poor metabolizers as the subjects revealed that the ratio of risperidone/ 9-hydroxyrisperidone was strongly dependent on CYP2D6 genotypes [30]. The present results again showed that CYP2D6 genotypes greatly affected the ratios of risperidone/9hydroxyrisperidone even among extensive metabolizers (Fig. 4, left hand). Although previous preliminary in vitro study using human liver microsomes [12] showed that the formation of 9-hydroxyrisperidone was catalyzed not only by CYP2D6 but also by CYP3A4, it is most likely that 9-hydroxylation, the major metabolic pathway of risperidone, is mainly dependent on CYP2D6 activity in clinical situations. This has been confirmed by our recent in vitro study using low substrate concentrations [13]. In the present study 2, significant intraindividual changes were observed in plasma concentrations of both risperidone and 9-hydroxyrisperidone during carbamazepine coadministration. This is in line with the previous report showing that plasma concentrations of risperidone and 9-hydroxyrisperidone in subjects receiving combination therapy with risperidone and carbamazepine are lower than those receiving risperidone alone [31]. It is likely that isozyme(s), e.g., CYP3A4, induced by carbamazepine is (are) involved in the metabolism of risperidone and 9-hydroxyrisperidone. On the other hand, the concentration ratios of risperidone/9-hydroxyrisperidone remained unchanged irrespective of coadministration or withdrawal of carbamazepine. These findings are because of the fact that 9-hydroxylation of risperidone is in principle CYP2D6-dependent and is scarcely affected by increased CYP3A4 activity during carbamazepine coadministration.
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The decreased risperidone concentrations by carbamazepine coadministration are unlikely due to enhanced 9-hydroxylation of risperidone since the concentrations of 9hydroxyrisperidone also significantly decreased in the present study 2. It is rather suggested that carbamazepine enhances other metabolic pathways of risperidone e.g., alicyclic dehydroxylation and/or oxdative N-dealkylation, probably via induction of CYP3A4. Furthermore, the changes in risperidone concentrations before and after carbamazepine coadministration were also closely associated with CYP2D6 genotypes (Fig. 4, middle hand). Provided that the ratio of risperidone/9-hydroxyrisperidone is an index of CYP2D6 activity, this finding implies that carbamazepine coadministration has a stronger impact on risperidone metabolism in subjects with less activity of CYP2D6. This is supported by a case report in which coadministration of carbamzepine in a poor CYP2D6 metabolizer resulted in a decrease in plasma concentration of risperidone and 9-hydroxyrisperidone [32]. In such cases, the metabolism catalyzed by carbamazepine inducible enzyme(s) other than CYP2D6 might have been originally an important compensation for limited capacity of CYP2D6-dependent 9-hydroxylation of risperidone. In conclusion, the present studies show that CYP2D6 genotype has an impact on drug interaction with risperidone, but not haloperidol. These findings suggest that CYP2D6 predominantly involved in risperidone metabolism, compared with haloperidol. Acknowledgements The authors are grateful to Yoshimasa Inoue (Pharmaceutical Research Division, Mitsubishi Welfarma) and Ronald de Vries (Department of Pharmacokinetics, RV, Janssen Research Foundation) for providing HPLC or LC – MS –MS technical support. References [1] L. Bertilsson, M.L. Dahl, B. Ekqvist, A. Llerena, Disposition of the neuroleptics perphenazine, zuclopenthixol, and haloperidol cosegregates with polymorphic debrisoquine hydroxylation, Psychopharmacol. Ser. 10 (1993) 230 – 237. [2] M.L. Huang, A. Van Peer, R. Woestenborghs, R. De Coster, J. Heykants, A.A. Jansen, Z. Zylicz, H.W. Visscher, J.H. Jonkman, Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects, Clin. Pharmacol. Ther. 54 (3) (1993) 257 – 268. [3] A. Llerena, R. Berecz, A. de la Rubia, M.J. Norberto, J. Benitez, Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity, Ther. Drug Monit. 22 (4) (2000) 397 – 401. [4] R.A. Branch, A. Adedoyin, R.F. Frye, J.W. Wilson, M. Romkes, In vivo modulation of CYP enzymes by quinidine and rifampin, Clin. Pharmacol. Ther. 68 (4) (2000) 401 – 411. [5] U. Jeppesen, L.F. Gram, K. Vistisen, S. Loft, H.E. Poulsen, K. Brosen, Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine, Eur. J. Clin. Pharmacol. 51 (1) (1996) 73 – 77. [6] J. Kallio, R. Huupponen, M. Seppala, E. Sako, E. Iisalo, The effects of beta-adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine, Br. J. Clin. Pharmacol. 30 (4) (1990) 638 – 643. [7] L.P. Pan, P. Wijnant, C. De Vriendt, M.T. Rosseel, F.M. Belpaire, Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol, Br. J. Clin. Pharmacol. 44 (6) (1997) 557 – 564. [8] J. Fang, G.B. Baker, P.H. Silverstone, R.T. Coutts, Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol, Cell. Mol. Neurobiol. 17 (2) (1997) 227 – 233.
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