Risperidone (RIS) is metabolized primarily by 9-hydroxylation

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1 BRIEF REPORT Effects of CYP2D6 and CYP3A5 Genotypes on the Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone in Korean Schizophrenic Patients Rhee-Hun Kang, MD, PhD,* Sun-Min Jung, MD, PhD,þ Kyoung-Ah Kim, PhD,Þ Duk-Ki Lee, MD, PhD,þ Hyun-Kee Cho, MD, PhD,þ Bong-Joo Jung, MD, PhD,þ Young-Ku Kim, MD, PhD,* Seung-Hyun Kim, MD, PhD,* Changsu Han, MD, PhD,* Min-Soo Lee, MD, PhD,* and Ji-Young Park, MD, PhDÞ Abstract: This study was conducted to evaluate the effects of the CYP2D6 and CYP3A5 genotypes on the steady-state plasma levels of risperidone (RIS), 9-hydroxyrisperidone (9-OH-RIS), and the active moiety (RIS plus 9-OH-RIS) in Korean schizophrenic patients. Sixtyfour Korean schizophrenic patients were enrolled. CYP2D6 and CYP3A5 genotypes were determined, and the plasma levels of RIS and 9-OH-RIS were measured using high-performance liquid chromatography. The dose-normalized plasma concentrations of RIS, 9-OH-RIS, and the active moiety were compared according to the CYP2D6 and CYP3A5 genotypes. Among the patients, 57 were CYP2D6 extensive metabolizers (EMs; CYP2D6*1/*1, *1/*10, and *10/*10) and 7 were CYP2D6 poor metabolizers (PMs; CYP2D6*1/*5 and *10/*5). For the CYP3A5 genotype, 30 patients were CYP3A5*1 expressors (*1/*1 [n = 1] and *1/*3 [n = 29]) and 34 patients were CYP3A5 nonexpressors (*3/*3). The plasma levels of RIS (2.03 ng/ml per milligram for EMs vs 5.57 ng/ml per milligram for PMs, P G 0.001) and 9-OH-RIS (5.06 ng/ml per milligram for EMs vs 0.22 ng/ml per milligram for PMs, P G 0.001) were significantly different among CYP2D6 genotype groups, but the CYP2D6 EMs (7.09 ng/ml per milligram) and PMs (5.79 ng/ ml per milligram) did not show no difference in the levels of the active moiety (P = 0.470). CYP3A5 nonexpressors exhibited higher plasma concentrations of both RIS and 9-OH-RIS than its expressors. In the case of 9-OH-RIS, CYP3A5 nonexpressors exhibited significantly higher concentrations than CYP3A5 expressors (5.42 vs 3.51 ng/ml per milligram, P = 0.022). In addition, concentrations of the active moiety were also significantly different between the CYP3A5 nonexpressors (8.39 ng/ml per milligram) and expressors (5.30 ng/ml per milligram, P = 0.005). In conclusion, both CYP2D6 and CYP3A5 genotypes affected plasma levels of RIS and 9-OH-RIS, whereas the active moiety levels were influenced only by the CYP3A5 genotype but not by the CYP2D6 genotype. Key Words: risperidone, cytochrome P450 2D6 (CYP2D6), cytochrome P450 3A5 (CYP3A5), 9-hydroxyrisperidone, pharmacogenetics (J Clin Psychopharmacol 2009;29: 272Y277) From the Departments of *Psychiatry and Clinical Pharmacology & Toxicology, Korea University College of Medicine, Seoul; and Department of Psychiatry, Yangsan Neuropsychiatric Hospital, Yangsan, Korea. Received August 20, 2008; accepted after revision February 24, Reprints: Ji-Young Park, MD, PhD, Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Sungbuk-gu, Seoul Korea ( jypark21@korea.ac.kr). This study was supported by grants of the Korea Health 21 R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A and no. 03-PJ10-PG13-GD , A050047). Drs Kang and S.-M. Jung contributed equally to this study. Copyright * 2009 by Lippincott Williams & Wilkins ISSN: DOI: /JCP.0b013e3181a289e0 Risperidone (RIS) is metabolized primarily by 9-hydroxylation into the active metabolite 9-hydroxyrisperidone (9-OH- RIS). 1 Many in vivo and in vitro studies have revealed that CYP2D6 is primarily involved in this metabolism. 2 In addition, polymorphic CYP2D6 genotypes have shown to influence both RIS and 9-OH-RIS levels. 3Y5 Although CYP3A is also involved in the 9-hydroxylation of RIS, 6 it is believed that its involvement is minor, and therefore, only CYP2D6 is considered to be the clinically important drug-metabolizing enzyme that modulates the plasma levels of RIS and 9-OH-RIS. However, several reports have recently suggested that CYP3A might be involved substantially in the metabolism of RIS irrespective of 9-hydroxylation. Rifampin 7 and carbamazepine, 8,9 CYP3A inducers, reduced both RIS and 9-OH-RIS levels, whereas itraconazole, 10 a CYP3A inhibitor, elevated their levels concurrently. The CYP3A family including CYP3A4, CYP3A5, CYP3A7, and CYP3A43 exhibits broad substrate specificity and metabolizes more than 50% of all pharmaceutical drugs. 11 The CYP3A5 protein is polymorphically expressed in the liver and intestines, and several genetic variants were identified. 12 Of these, CYP3A5*3, a 6986A9G substitution in intron 3, is the single most common allele within the major ethnic groups. 13,14 CYP3A5*3 has been shown to modulate the pharmacokinetic characteristics of various CYP3A substrates. 15Y17 Supposed that RIS is a substrate of CYP3A5, its genetic polymorphism might modulate blood levels of RIS. However, despite many studies revealing the role of the CYP2D6 genotype in the blood levels of RIS, little is known about the pharmacogenetic effect of the CYP3A5 genotype. In this study, we assessed the role of CYP2D6 and CYP3A5 genotypes in the plasma concentrations of both RIS and 9-OH- RIS in schizophrenic patients. METHODS Subjects and Study Design Sixty-four Korean schizophrenic patients who fulfilled the criteria for schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria) were studied. Blood samples for the determination of the plasma concentrations of RIS and 9-OH-RIS were drawn more than 2 months after initiation of RIS treatment at 8 A.M., before the next dose. All patients received RIS at a daily dosage ranging from 2 to 16 mg/d (mean [SD] dose, 5.3 [3.2] mg) orally in 2 divided daily administration. The demographic attributes of the patients are presented in Table 1. Patients on antipsychotics, barbiturates, or carbamazepine as subordinate prescriptions were not included because these drugs are known to modulate the RIS metabolism and its plasma levels. 18 Anticholinergics (procyclidine and benztropine) in usual doses were administered when patients Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009

2 Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009 CYP2D6 and CYP3A5 on RIS and 9-OH-RIS TABLE 1. Patients Demographic Data and Their Steady-State Dose-Normalized Concentrations (C/D) of RIS, 9-OH-RIS, Active Moiety, and Its Ratio According to Respective CYP2D6 and CYP3A5 Genotypes RIS/9-OH-RIS Ratio Active Moiety, ng/ml per mg 9-OH-RIS C/D, ng/ml per mg RIS C/D, ng/ml per mg Parameters n Sex (M/F) Age, yr Weight, kg CYP2D6 EMs *1/* / (11.4) 64.0 (11.0) 1.61 (2.25) 4.44 (2.47) 6.05 (3.52) 0.43 (0.69) *1/* / (8.9) 62.0 (13.7) 1.93 (1.77) 6.49 (5.09) 8.42 (6.37) 0.40 (0.42) *10/* / (12.0) 66.9 (7.5) 2.97 (0.73) 4.76 (3.33) 7.74 (4.37) 1.48 (2.03) Total 57 34/ (11.1) 64.2 (11.0) 2.03 (2.29) 5.05 (3.57) 7.09 (4.65) 0.67 (1.20) PMs *1/*5 4 4/ (2.8) 67.7 (5.0) 4.54 (1.22) 0.19 (0.10) 4.72 (1.27) (13.58) *10/*5 3 3/ (5.0) 66.0 (3.0) 6.94 (2.35) 0.26 (0.11) 7.20 (2.46) (6.23) Total 7 7/ (3.9) 67.0 (4.0) 5.56 (0.05) 0.21 (0.10) 5.79 (2.13) 28.1 (10.2) P G0.001 G G0.001 CYP3A5 Expressors (*1/*1 or *1/*3) 30 19/ (10.5) 67.1 (10.5) 1.78 (1.93) 3.51 (2.48) 5.30 (2.64) 4.38 (10.8) Nonexpressors (*3/*3) 34 22/ (11.8) 61.5 (12.0) 2.97 (2.84) 5.42 (4.35) 8.39 (5.21) 3.05 (7.68) P Data are given as mean (SD). complained of autonomic adverse effects, whereas benzodiazepines (lorazepam and diazepam) were used to counteract any sleep disturbance. We did not find any report to demonstrate a substantial interaction of these drugs with RIS pharmacokinetically. The patients in this study did not take any cytochrome P450Ymodulating drugs or herbal remedies, particularly for CYP2D6 and CYP3A. This study was approved of by the local ethics committee of Yangsan Neuropsychiatric Hospital, Yangsan, Korea. The patients were aware of the purpose of the study and provided oral and written informed consent for participation. CYP2D6 and CYP3A5 Genotyping Methods Genomic DNA for the determination of the CYP2D6 and CYP3A5 genotypes was isolated from blood. All patients were screened with allele-specific polymerase chain reaction (PCR), extra long PCR, and PCRYrestriction fragment length polymorphism methods to determine the CYP2D6 alleles *2, *2xN, *3, *4, *5, and *10 that are frequently found in Asians. 10,19 The presence of the CYP3A5*3 allele was also determined by PCRY restriction fragment length polymorphism, as previously reported. 20 We only identified patients with *1, *5, or*10 for CYP2D6 genotypes. Therefore, patients carrying CYP2D6*1/*1 (n = 28), *1/*10 (n = 15), and *10/*10 (n = 14) were classified as extensive metabolizers (EMs), and those carrying CYP2D6*1/*5 (n = 4) or *10/*5 (n = 3) were classified as poor metabolizers (PMs). For CYP3A5, we found only 1 patient with CYP3A5*1/*1, so we classified the patients into CYP3A5 expressors (*1/*1 [n = 1] and *1/*3 [n = 29]) and nonexpressors (*3/*3 [n = 34]). Analysis of Plasma Concentrations of RIS and 9-OH-RIS The plasma concentrations of RIS and 9-OH-RIS were measured using a validated high-performance liquid chromatography method according to a previously reported method. 10 The interday and intraday coefficients of variation of the quality controls were less than 11%. Statistical Analysis The data are expressed as mean (SD), and differences at P G 0.05 were considered significant. After normality test, comparisons between CYP3A5 expressors and nonexpressors and between CYP2D6 EMs and PMs were assessed using unpaired Student t test or Wilcoxon signed rank sum test. Statistical comparisons between combined CYP2D6/CYP3A5 genotype groups were made with 1-way analysis of variance (ANOVA) or Kruskal-Wallis 1-way ANOVA on ranks, and multiple post hoc comparisons were performed after normality test. Before the ANOVA test, genotype groups were compared by performance of an analysis of covariance with an effect term for both CYP2D6 and CYP3A5 genotypes and with age and sex as covariates. Interactions between genotype and each of the covariates were not statistically significant. Statistical analyses were performed using the statistical software SAS version 9.13 (SAS Institute, Cary, NC). RESULTS When we assessed the effect of the CYP2D6 genotype on plasma levels of both RIS and 9-OH-RIS after dose normalization, the levels of both RIS and 9-OH-RIS showed a difference between CYP2D6 genotype groups (P values G 0.001; Table 1 and Fig. 1). CYP2D6 PMs exhibited higher RIS levels than EMs, whereas those of 9-OH-RIS were lower in CYP2D6 PMs than EMs (Fig. 1). The metabolic ratios (MRs) of RIS/9-OH-RIS varied largely according to CYP2D6 genotypes (P G 0.001), but * 2009 Lippincott Williams & Wilkins 273

3 Kang et al Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009 FIGURE 1. Comparison of dose-normalized plasma levels of RIS (A, D), 9-OH-RIS (B, E), and active moiety (C, F) according to CYP2D6 and CYP3A5 genotypes. The bar indicates the average value. Expressors, patients carrying CYP3A5*1/*1 or *1/*3; nonexpressors, patients carrying CYP3A5*3/*3; EM, patients carrying CYP2D6*1/*1, *1/*10, or*10/*10; PM, patients carrying CYP2D6*1/*5 or *10/*5. the levels of the active moiety did not differ between CYP2D6 EMs and PMs (Table 1 and Fig. 1). The CYP3A5 nonexpressors exhibited higher plasma levels of both RIS and 9-OH-RIS than the expressors (Table 1 and Fig. 1). In the case of active moiety, the CYP3A5 nonexpressors (8.39 ng/ml per milligram) displayed higher levels than its expressors (5.30 ng/ml per milligram, P = 0.005). However, the CYP3A5 genotype did not influence the MRs of RIS/9-OH-RIS different from the CYP2D6 genotype (P = 0.571; Table 1). When we assessed the combined effects of CYP2D6 and CYP3A5 genotypes on RIS, 9-OH-RIS, and active moiety levels, both RIS and 9-OH-RIS levels were dependent on CYP2D6 and CYP3A5 genotypes, but active moiety levels were affected only by CYP3A5 genotypes and not by CYP2D6 genotypes (Table 2 and Fig. 2). DISCUSSION In this study, we evaluated the effects of CYP2D6 and CYP3A5 genotypes on plasma levels of RIS and 9-OH-RIS in schizophrenic patients. Although the plasma levels of RIS and 9- OH-RIS were affected by both CYP2D6 and CYP3A5 genotypes, the CYP3A5 genotype but not the CYP2D6 genotype influenced the active moiety levels in this population. Risperidone is extensively metabolized in the liver mainly by CYP2D6 and in part by CYP3A into 9-OH-RIS. 1,6 Because CYP2D6 is the main drug-metabolizing enzyme for 9-hydroxylation of RIS, 1,6 CYP2D6 PMs showed metabolic disturbances in 9-hydroxylation of RIS compared with CYP2D6 EMs. These metabolic disturbances translated into higher RIS levels but lower 9-OH-RIS levels. Consistently, the MRs of RIS/9-OH-RIS, indicating CYP2D6 activity, exhibited prominent differences between CYP2D6 genotype groups in this study. Previous studies also reported similar findings. 3,4,10 However, unlike the CYP2D6 genotype, the CYP3A5 genotype did not influence its MRs in this study. Although we failed to demonstrate a significant difference in RIS levels between CYP3A5 genotypes, RIS tended to be higher in CYP3A5 nonexpressors. In the cases of 9-OH-RIS and the active moiety, CYP3A5 nonexpressors exhibited significantly higher levels than its expressors. Previously, itraconazole, a CYP3A inhibitor, elevated concurrently both RIS and 9-OH-RIS levels without a difference in MRs. 10 These findings suggested that although CYP3A including CYP3A5 may be involved in the formation of 9-OH-RIS, 2 the CYP3A5 genotype is not a determinant in this metabolism, and thus, other metabolic pathways might be involved in the metabolism of RIS. 21, * 2009 Lippincott Williams & Wilkins

4 Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009 CYP2D6 and CYP3A5 on RIS and 9-OH-RIS TABLE 2. Comparisons of Steady-State Dose-Normalized Concentrations (C/D) of RIS, 9-OH-RIS, Active Moiety, and Its Ratio According to Combined CYP2D6 and CYP3A5 Genotypes CYP2D6 Genotype EM (*1/*1, *1/*10, or*10/*10) PM (*1/*5 or *10/*5) CYP3A5 Genotype Expressors (*1/*1 or *1/*3) Nonexpressors (*3/*3) Expressors (*1/*1 or *1/*3) Nonexpressors (*3/*3) n RIS C/D, ng/ml per mg 1.33 (1.58) 2.61 (2.63) 4.74 (1.38) 6.66 (2.58) * 9-OH-RIS C/D, ng/ml per mg 4.03 (2.25) 5.92 (4.23) 0.17 (0.06) 0.27 (0.12) Active moiety, ng/ml per mg 5.36 (2.80) 8.53 (5.40) 4.92 (1.40) 6.94 (2.69) RIS/9-OH-RIS ratio 0.49 (0.78) 0.83 (1.45) 29.7 (12.4) 26.0 (8.42) G0.0001* *P G 0.05 for comparison between CYP2D6 EM/CYP3A5 expressors and CYP2D6 PM/CYP3A5 expressors. P G 0.05 for comparison between CYP2D6 EM/CYP3A5 expressors and CYP2D6 PM/CYP3A5 nonexpressors. P G 0.05 for comparison between CYP2D6 EM/CYP3A5 nonexpressors and CYP2D6 PM/CYP3A5 nonexpressors. P G 0.05 for comparison between CYP2D6 EM/CYP3A5 nonexpressors and CYP2D6 PM/CYP3A5 expressors. P G 0.05 for comparison between CYP2D6 EM/CYP3A5 expressors and CYP2D6 EM/CYP3A5 expressors. P 9-Hydroxyrisperidone exhibits pharmacological activity that is approximately equal to the parent compound, RIS, in its dopamine receptor affinity. 21,23 Therefore, the active moiety is considered to be most clinically relevant. In addition, the active moiety is known to contribute to the overall antipsychotic effects of RIS 23,24 and to correlate well with the occurrence of parkinsonian adverse effects. 25 Consistent with previous studies, 3,4 in this study, CYP2D6 PMs exhibited higher RIS but lower 9-OH- RIS concentrations compared with CYP2D6 EMs. As a result, these patients showed higher MRs of RIS/9-OH-RIS. However, when we compared the levels of the active moiety among the CYP2D6 genotype groups, the values obtained were similar, and there was no significant difference between them. Considering that the overall antipsychotic effects are related to the levels of the active moiety, 23,24 the CYP2D6 genotype may not be the major factor that determines the variability of the clinical response to RIS. Likewise, previous studies revealed that the CYP2D6 genotype had little effect on the variability of active moiety levels of RIS and on its clinical responses. 3,26 Previously, it has been reported that polymorphic CYP2D6 and the levels of active moiety were related to adverse effects. 27 However, we did not assess the rate of response and adverse events in this study. Therefore, it is our limitation that we did not assess whether both CYP2D6 and CYP3A5 genotypes were directly related to the response or adverse events of RIS. Among the CYP3A5 polymorphisms, the CYP3A5*3 allele leads to alternative splicing and protein truncation and thus affects the expression of CYP3A5. 14 The resultant functional defect in CYP3A5 affects the disposition of various CYP3A substrates. 15Y17,28,29 Unlike the effect of the CYP2D6 genotypes, our study showed that the active moiety levels of CYP3A5 nonexpressors were higher than those of CYP3A5 expressors, suggesting that the CYP3A5 genotype is a determinant in modulating the active moiety levels. Itraconazole, a CYP3A inhibitor, elevated the concentrations of RIS, 9-OH-RIS, and the active moiety. 10 Conversely, CYP3A inducers such as rifampin and carbamazepine reduced these levels simultaneously. 7Y9 However, these CYP3A inhibitor and inducers did not exhibit no effect on MRs of RIS/9-OH-RIS. The results of the present study suggested that CYP3A including CYP3A5 might be FIGURE 2. Comparison of dose-normalized plasma concentrations of RIS (A), 9-OH-RIS (B), and active moiety (C) according to combined CYP2D6/CYP3A5 genotypes. The bar indicates the average value. Expressors, patients carrying CYP3A5*1/*1 or *1/*3; nonexpressors, patients carrying CYP3A5*3/*3; EM, patients carrying CYP2D6*1/*1, *1/*10, or*10/*10; PM, patients carrying CYP2D6*1/*5 or *10/*5. * 2009 Lippincott Williams & Wilkins 275

5 Kang et al Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009 involved in the different metabolic pathway(s) of RIS other than RIS 9-hydroxylation. 21,22 Further studies are warranted to reveal which metabolic pathway(s) are involved in relation to CYP3A. A contrasting report by Leon et al 30 showed that the CYP3A PMs phenotype probably played no role in modifying the RIS levels. However, although the authors examined the relationship between RIS dosing and RIS/9-OH-RIS ratios according to CYP3A5 genotypes, they did not assess the association of these parameters with the levels of the active moiety. Similar to our results, they showed that RIS/9-OH-RIS ratios exhibited no difference between CYP3A5 genotype groups. In addition, they reported that CYP3A inducers or inhibitors might have clinical relevance to RIS treatment, thus supporting the evidence of involvement of CYP3A in the metabolism of RIS. 30 Considering that both polymorphic genotypes and drug interactions 7,10,18,31 can modulate the RIS, 9-OH-RIS, and active moiety levels, the disposition of RIS might be affected additively when combined. CYP2D6 EMs and CYP3A5 nonexpressors showed relatively higher levels of 9-OH-RIS than CYP2D6 PMs and CYP3A5 expressors, respectively. The formation of 9-OH-RIS is stereoselective with respect to the activity of CYP2D6 and CYP3A5. 6 However, there is no available information about the pharmacological activity of 2 enantiomers of 9-OH-RIS. Therefore, further studies on their pharmacological activities and the difference in the disposition of 2 enantiomers by pharmacogenetic effects are needed. It has been suggested that although RIS shows a curvilinear dose-response relationship over the range 1 to 16 mg/d, with maximum antipsychotic activity apparently occurring at dosages of 4 to 8 mg/d, the suggested therapeutic range of the active moiety is narrow (20-60 ng/ml). 32,33 Therefore, to obtain the optimal therapeutic levels of the active moiety in patients, the presence of the CYP3A5 genotype must be considered as a factor that can cause interindividual variability in RIS levels. The CYP3A5 genotype may play a crucial role in the determination of the levels of the active moiety, leading to possible alterations in clinical symptoms or adverse effects of RIS. In this study, although we identified the effects of CYP2D6 and CYP3A5 genotypes on the variability of RIS, 9-OH-RIS, and the active moiety, the levels of RIS and 9-OH-RIS still showed large interindividual variability within the same genotype groups. It suggests that besides CYP2D6 and CYP3A5 genotypes, other factor(s) that influence RIS disposition should be considered. Similar to 9-OH-RIS and the active moiety, RIS levels in CYP3A5 nonexpressors were higher than those in expressors but failed to show a significant difference. A small sample might cause largely interindividual variability in RIS levels. In conclusion, both CYP2D6 and CYP3A5 genotypes affected the plasma concentrations of RIS and 9-OH-RIS, whereas the levels of the active moiety were influenced only by the CYP3A5 genotype and not by the CYP2D6 genotype in Korean schizophrenic patients. Thus, particular interpretation of the CYP3A5 genotype may be advisable in patients treated with RIS to optimize blood levels of RIS. AUTHOR DISCLOSURE INFORMATION The authors have no conflict of interest to declare. REFERENCES 1. Mannens G, Huang ML, Meuldermans W, et al. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos. 1993;21:1134Y Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol. 1999;359:147Y Mihara K, Kondo T, Yasui-Furukori N, et al. Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther Drug Monit. 2003;25: 287Y Yasui-Furukori N, Mihara K, Kondo T, et al. Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia. J Clin Pharmacol. 2003;43:122Y Berecz R, Llerena A, de la Rubia A, et al. Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients. Pharmacopsychiatry. 2002;35:231Y Yasui-Furukori N, Hidestrand M, Spina E, et al. Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001;29:1263Y Kim KA, Park PW, Liu KH, et al. Effect of rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics of risperidone. J Clin Pharmacol. 2008;48:66Y Ono S, Mihara K, Suzuki A, et al. Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes. Psychopharmacology (Berl). 2002;162: 50Y Spina E, Avenoso A, Facciola G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther Drug Monit. 2000;22:481Y Jung SM, Kim KA, Cho HK, et al. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. Clin Pharmacol Ther. 2005;78:520Y Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996;6:1Y CYP3A5 allele nomenclature. Available at: cyp3a5.htm. Accessed August 1, Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001;11:773Y Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383Y Kim KA, Park PW, Lee OJ, et al. Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J Clin Pharmacol. 2007;47:87Y Kim KA, Park PW, Lee OJ, et al. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects. Clin Pharmacol Ther. 2006;80:646Y Park JY, Kim KA, Park PW, et al. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. Clin Pharmacol Ther. 2006;79:590Y DeVane CL, Nemeroff CB. An evaluation of risperidone drug interactions. J Clin Psychopharmacol. 2001;21:408Y Park JY, Shon JH, Kim KA, et al. Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. J Clin Psychopharmacol. 2006;26:135Y Kim KA, Park PW, Park JY. Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects. Eur J Clin Pharmacol. 2008;64:589Y Megens AA, Awouters FH, Schotte A, et al. Survey on the * 2009 Lippincott Williams & Wilkins

6 Journal of Clinical Psychopharmacology & Volume 29, Number 3, June 2009 CYP2D6 and CYP3A5 on RIS and 9-OH-RIS pharmacodynamics of the new antipsychotic risperidone. Psychopharmacology (Berl). 1994;114:9Y DeVane C, Markowitz J. Drugs as substrates of metabolic enzymes: antipsychotics. In: Levy R, ed. Metabolic Drug Interactions. Philadelphia, PA: Lippincott-Raven; 2000:245Y van Beijsterveldt LE, Geerts RJ, Leysen JE, et al. Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology (Berl). 1994;114:53Y Huang ML, Van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther. 1993;54:257Y Spina E, Avenoso A, Facciola G, et al. Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology (Berl). 2001;153:238Y Llerena A, Berecz R, Dorado P, et al. QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations. J Psychopharmacol. 2004;18:189Y Scordo MG, Spina E, Romeo P, et al. CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients. Eur J Clin Pharmacol. 2000;56:679Y Min DI, Ellingrod VL, Marsh S, et al. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit. 2004;26:524Y Frohlich M, Hoffmann MM, Burhenne J, et al. Association of the CYP3A5 A6986G (CYP3A5*3) polymorphism with saquinavir pharmacokinetics. Br J Clin Pharmacol. 2004;58:443Y Leon J, Susce MT, Pan RM, et al. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry. 2007;40:93Y Lane HY, Chang WH. Risperidone-carbamazepine interactions: is cytochrome P450 3A involved? J Clin Psychiatry. 1998;59:430Y Hiemke C, Dragicevic A, Grunder G, et al. Therapeutic monitoring of new antipsychotic drugs. Ther Drug Monit. 2004;26:156Y Riedel M, Schwarz MJ, Strassnig M, et al. Risperidone plasma levels, clinical response and side-effects. Eur Arch Psychiatry Clin Neurosci. 2005;255:261Y268. * 2009 Lippincott Williams & Wilkins 277