A Study of Genetic (CYP2D6 and ABCB1) and Environmental (Drug Inhibitors and Inducers) Variables That May Influence Plasma Risperidone Levels

Abstract

Risperidone (R) is metabolized to 9-hydroxyrisperidone (9-OHR) by cytochrome P450 2D6 (CYP2D6). The main objective of this naturalistic study was to investigate the variables associated with two plasma ratios: the plasma R:9-OHR concentration ratio and the total concentration-to-dose (C:D) ratio. These ratios were studied as continuous measures by linear regression analyses and as three dichotomous variables in logistic regression analyses: R:9-OHR ratio >1 (indicative of lack of CYP2D6 activity), C:D ratio >14 (indicative of diminished R elimination), and C:D ratio <3.5 (indicative of increased R elimination). Plasma R levels; genotypes for CYP2D6, CYP3A5; and ABCB1 genes, and co-medication, including CYP inhibitors and CYP3A inducers, were studied in 277 patients. Almost all CYP2D6 poor metabolizers (PMs) had an inverted R:9-OHR ratio (>1). Having a CYP2D6 PM phenotype was strongly associated with a C:D ratio >14 (OR=8.2; 95% confidence interval [CI]=2.0-32.7), indicating diminished R elimination. CYP2D6 ultrarapid metabolizers (UMs) did not exhibit an increased R elimination. Some ABCB1 (or MDR1) variants were significantly associated with increased R:9-OHR ratios and decreased C:D ratios, but the results were neither consistent nor robust. Taking CYP inhibitors was significantly associated with a C:D ratio >14 (OR=3.8; CI=1.7-8.7) and with an inverted R:9-OHR ratio. Taking CYP3A inducers was significantly associated with a C:D ratio <3.5 (OR=41.8; CI=12.7-138), indicating increased R elimination. Female gender and old age appeared to be associated with a lower R elimination. Our study indicated that the CYP2D6 PM phenotype may have a major role in personalizing R doses, whereas the CYP3A5 PM phenotype probably has no role. CYP inducers and inhibitors appear to be relevant to R dosing. New studies are needed, particularly to further assess the role of the CYP2D6 UM phenotype and ABCB1 variants in R pharmacokinetics.

Keywords

risperidone - CYP2D6 - CYP3A5 - ABCB1 - inhibitor - inducer

References

• 1 Aichhorn W, Weiss U, Marksteiner J, Kemmeler G, Walch T, Zernig G. et al . Influence of age and gender on risperidone plasma concentrations.  J Psychopharmacol. 2005;  19 395-401
• 2 Anderson CB, True JE, Ereshefsky L, Miller AL, Peters BL, Velligan DI. Risperidone dose, plasma levels and response. 1993 New Research Program and Abstracts: American Psychiatric Association Annual Meeting. San Francisco CA 1993 (NR 217): 113
• 3 Barnhill J, Susce MT, Diaz FJ, de Leon J. Risperidone half-life in a patient taking paroxetine: a case report.  Pharmacopsychiatry. 2005;  38 223-225
• 4 Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M. et al . The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.  Pharmacopsychiatry. 2004;  37 243-256
• 5 Bork J, Rogers T, Wedlund P, de Leon J. A pilot study of risperidone metabolism: the role of cytochrome P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
• 6 Cai WM, Nikoloff DM, Pan RM, de Leon J, Fanti P, Fairchild M. et al . CYP2D6 genetic variations in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing.  Pharmacogenomics J. 2006;  6 343-350
• 7 Candiotti KA, Birnbach DJ, Lubarsky DA, Nhuch F, Kamat A, Koch WH. et al . The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?.  Anesthesiology. 2005;  102 543-549
• 8 Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M. et al . Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.  Clin Pharmacol Ther. 2001;  69 169-174
• 9 Chou WH, Yan FX, Robbins-Weilert DK, Ryder TB, Liu WW, Perbost C. et al . Comparison of two CYP2D6 genotyping methods and assessments of genotype-phenotype relationships.  Clin Chemistry. 2003;  49 542-551
• 10 de Leon J. The AmpliChip CYP450 Test: personalized medicine has arrived in psychiatry.  Expert Rev Mol Diagn. 2006;  6 277-286
• 11 de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics.  Psychosomatics. 2005;  46 262-273
• 12 de Leon J, Bork JA. Risperidone and the cytochrome P4503A (letter).  J. Clin Psychiatry. 1997;  58 450
• 13 de Leon J, Susce MT, Murray-Carmichael E. The AmpliChip CYP450 genotyping test: integrating a new clinical tool.  Mol Diag Ther. 2006;  10 135-151
• 14 de Leon J, Susce MT, Pan RM, Fairchild M, Koch W, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation.  J Clin Psychiatry. 2005;  66 15-27
• 15 de Leon J, Susce MT, Pan RM, Fairchild M, Koch W, Wedlund PJ. Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness.  J Clin Psychopharmacol. 2005;  25 448-456
• 16 Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics.  J Clin Psychiatry. 1996;  57 ((Suppl. 11)) 12-25
• 17 Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  359 147-151
• 18 Hendset M, Haslemo T, Rudberg I, Refsum H, Molden E. The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs.  Pharmacopsychiatry. 2006;  39 121-127
• 19 Heykants J, Huang ML, Mannens G, Meudermans W, Snoeck E, Van Beijsterveldt L. et al . The pharmacokinetics of risperidone in humans: a summary.  J Clin Psychiatry. 1994;  55 ((Suppl. 5)) 13-17
• 20 Huang M, Van Peer A, Woestenborghs R, De Coster RD, Heykants J, Jansen AAI. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
• 21 Muñoz A, Xu J. Models for the incubation of AIDS and variations according to age and period.  Stat Med. 1996;  15 2459-2473
• 22 Nakagami T, Yasui-Furukori N, Saito M, Tateishi T, Kaneo S. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition.  Clin Pharmacol Ther. 2005;  78 43-51
• 23 Raedler TJ, Schreiner A, Naber D, Wiedemann K. Gender-specific effects in the treatment of acute schizophrenia with risperidone.  Pharmacopsychiatry. 2006;  39 171-174
• 24 Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter.  Annu Rev Pharmacol Toxicol. 2003;  43 285-307
• 25 SPSS Inc .SPSS 9.0, Applications Guide. Chicago, IL: SPPS Inc 1999
• 26 Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL. The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein.  Int J Neuropsychopharmacology. 2004;  7 415-419
• 27 Woestenborghs R, Lorreyne W, Van Rompaey F, Heykants J. Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography.  J Chromatogr. 1992;  583 223-230
• 28 Weber CC, Kressmann S, Ott M, Fricker G, Muller WE. Inhibition of P-glycoprotein function by several antidepressants may not contribute to clinical efficacy.  Pharmacopsychiatry. 2005;  38 293-300
• 29 Woodward M. Epidemiology. Study design and data analysis. Boca Raton, FL: Chapman and Hall/CRC 1999
• 30 Yasui-Fururoki N, Mihara K, Takahata T, Suzuki A, Nakagami T, De Vries R. et al . Effect of various factors on steady-plasma concentration of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes.  Br J Clin Pharmacol. 2003;  57 569-575
• 31 Zheng H, Schuetz E, Zeevi A, Zhang J, McCurry K, Webber S. et al . Sequential analysis of tacrolimus dosing in adult lung transplant patients with ABCB1 haplotypes.  J Clin Pharmacol. 2005;  45 404-410

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