Skip to main content
SpringerLink
Log in

Long-Term Therapeutic Drug Monitoring of Risperidone and Olanzapine Identifies Altered Steady-State Pharmacokinetics

A Clinical, Two-Group, Naturalistic Study

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and objective: Conflicting therapeutic drug monitoring (TDM) results have been reported for risperidone and olanzapine. This study set out to examine the long-term pharmacokinetics of risperidone and olanzapine in a locked skilled nursing facility where medication administration was controlled by nursing staff.

Methods: TDM was performed in a long-term treatment protocol for risperidone and olanzapine in 67 refractory chronic schizophrenic patients in a locked, skilled nursing facility. TDM was performed 632 times in the risperidone group of 34 patients and 563 times in the olanzapine group of 33 patients. The logarithm of plasma concentrations were analysed through time by piecewise linear mixed model regressions adjusted for the logarithm of dose.

Results: We found risperidone plasma concentration/dose ratio (C/D) accumulation peaks of 49% at 2 months (from baseline concentration) and 9-hydroxy-risperidone and total moiety C/D accumulation peaks of 66% and 55% above the 2-month level at 6 months, which are somewhat similar to those found in our prior study that included a subset of data points analysed here. The risperidone conversion to 9-hydroxy-risperidone by cytochrome P450 (CYP) 2D6 suggests CYP2D6 inhibition or DNA down-regulation in the first 2 months. Olanzapine showed a C/D accumulation peak at 4 months of 31% above baseline, and a slower increase to 47% above baseline at 18 months with no clear plateau.

Conclusion: We identified five potential perturbations in the pharmacokinetics of risperidone and olanzapine that could potentially lead to adverse drug reactions. These long-term effects would not be captured by a standard 5-day pharmacokinetic TDM developmental testing model for antipsychotics, and a new model for characterizing variation in C/D by time course is therefore proposed. The time course of the accumulations identified suggests that both CYP inhibition and DNA regulatory mechanisms may be involved in the metabolism of these drugs. Long-term TDM can optimize treatment with risperidone and olanzapine and antipsychotics in general.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Darby JK, Pasta DJ, Dabiri L, et al. Haloperidol dose and blood level variability: toxicity and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting. J Clin Psychopharmacol 1995; 15(5): 334–40

    Article  PubMed  CAS  Google Scholar 

  2. Darby JK, Pasta DJ, Elfand L, et al. Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting. J Clin Psychopharmacol 1997; 17(6): 478–84

    Article  PubMed  CAS  Google Scholar 

  3. 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(3): 287–93

    Article  PubMed  CAS  Google Scholar 

  4. Nakagami T, Yasui-Furukori N, Saito M, et al. Thioridazine inhibits risperidone metabolism: a clinically relevant drug interaction. J Clin Psychopharmacol 2005; 25(1): 89–91

    Article  PubMed  Google Scholar 

  5. Jacubeit T, Drisch D, Weber E. Risk factors as reflected by an intensive drug monitoring system. Agents Actions 1990; 29 Suppl.: 117–25

    Article  CAS  Google Scholar 

  6. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients: results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324(6): 377–84

    Article  PubMed  CAS  Google Scholar 

  7. Leape LL, Bates DW, Cullen DJ, et al. Systems analysis of adverse drug events: ADE Prevention Study Group. JAMA 1995; 274(1): 35–43

    Article  PubMed  CAS  Google Scholar 

  8. Haack MJ, Bak ML, Beurskens R, et al. Toxic rise of clozapine plasma concentrations in relation to inflammation. Eur Neuro-psychopharmacol 2003; 13(5): 381–5

    Article  CAS  Google Scholar 

  9. de Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005; 66(1): 15–27

    Article  PubMed  Google Scholar 

  10. Beigneux AP, Moser AH, Shigenaga JK, et al. Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response. Biochem Biophys Res Commun 2002; 293(1): 145–9

    Article  PubMed  CAS  Google Scholar 

  11. Cheng PY, Morgan ET. Hepatic cytochrome P450 regulation in disease states. Curr Drug Metab 2001; 2(2): 165–83

    Article  PubMed  CAS  Google Scholar 

  12. Morgan ET. Suppression of constitutive cytochrome P-450 gene expression in livers of rats undergoing an acute phase response to endotoxin. Mol Pharmacol 1989; 36(5): 699–707

    PubMed  CAS  Google Scholar 

  13. Castberg I, Helle J, Aamo TO. Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline. Ther Drug Monit 2005; 27(5): 680–2

    Article  PubMed  Google Scholar 

  14. Jacobsen SA, Pies RW, Greenblatt DJ. Introduction to geriatric psychopharmacology. In: Jacobsen SA, Pies RW, Greenblatt DJ, editors. Handbook of geriatric psychopharmacology. Washington, DC: American Psychiatric Publishing, Inc., 2002: 1–26

  15. Ohyama K, Nakajima M, Suzuki M, et al. Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions. Br J Clin Pharmacol 2000; 49(3): 244–53

    Article  PubMed  CAS  Google Scholar 

  16. Kashima A, Funahashi M, Fukumoto K, et al. Pharmacokinetic characteristics of amiodarone in long-term oral therapy in Japanese population. Biol Pharm Bull 2005; 28(10): 1934–8

    Article  PubMed  CAS  Google Scholar 

  17. McEvoy G, Litvak K, Welsh OH. Cardiovascular drugs, amiodarone hydrochloride: American Hospital Formulary Service, drug information. Bethesda (MD): American Society of Hospital Pharmacists; 1990: 779

    Google Scholar 

  18. Pollak FT, Bouillon T, Shafer SL. Population pharmacokinetics of long-term oral amiodarone therapy. Clin Pharmacol Ther 2000; 67(6): 642–52

    Article  PubMed  CAS  Google Scholar 

  19. Kakiuchi Y, Kohda Y, Miyabe M, et al. Effect of plasma alphal-acid glycoprotein concentration on the accumulation of lidocaine metabolites during continuous epidural anesthesia in infants and children. Int J Clin Pharmacol Ther 1999; 37(10): 493–8

    PubMed  CAS  Google Scholar 

  20. Sawyer D. Cardiovascular II module, Lecture 38 [pamphlet] Pocatello (ID): Idaho State University, College of Pharmacy, 2004

  21. Voicu V, Mircioiu C, Jinga M, et al. Pharmacokinetic based adjustment of lidocaine antiarrhythmic schedule. Eur J Drug Metab Pharmacokinet 1994; 19(1): 33–6

    Article  PubMed  CAS  Google Scholar 

  22. Ray WA, Meredith S, Thapa PB, et al. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 2001; 58(12): 1161–7

    Article  PubMed  CAS  Google Scholar 

  23. Straus SM, Bleumink GS, Dieleman JP, et al. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med 2004; 164(12): 1293–7

    Article  PubMed  Google Scholar 

  24. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005; 353(22): 2335–41

    Article  PubMed  CAS  Google Scholar 

  25. Xu C, Li CY, Kong AN. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 2005; 28(3): 249–68

    Article  PubMed  CAS  Google Scholar 

  26. Choi E, Lee S, Yeom SY, et al. Characterization of activating signal cointegrator-2 as a novel transcriptional coactivator of the xenobiotic nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005; 19(7): 1711–9

    Article  PubMed  CAS  Google Scholar 

  27. Takeshita A, Taguchi M, Koibuchi N, et al. Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem 2002; 277(36): 32453–8

    Article  PubMed  CAS  Google Scholar 

  28. Yeowell HN, Waxman DJ, Wadhera A, et al. Suppression of the constitutive, male-specific rat hepatic cytochrome P-450 2c and its mRNA by 3,4,5,3’,4’,5’-hexachlorobiphenyl and 3-methylcholanthrene. Mol Pharmacol 1987; 32(3): 340–7

    PubMed  CAS  Google Scholar 

  29. Kretschmer XC, Baldwin WS. CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact 2005; 155(3): 111–28

    Article  PubMed  CAS  Google Scholar 

  30. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54(10): 1271–94

    Article  PubMed  CAS  Google Scholar 

  31. Morgan ET. Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos 2001; 29(3): 207–12

    PubMed  CAS  Google Scholar 

  32. Wang JS, DeVane CL, Gibson BB, et al. Population pharmacokinetic analysis of drug-drug interactions among risperidone, bupropion, and sertraline in CF1 mice. Psychopharmacology (Berl) 2006; 183(4): 490–9

    Article  CAS  Google Scholar 

  33. Linnet K. Glucuronidation of olanzapine by cDNA-expressed human UDP-glucuronosyltransferases and human liver micro-somes. Hum Psychopharmacol 2002; 17(5): 233–8

    Article  PubMed  CAS  Google Scholar 

  34. Doran A, Obach RS, Smith BJ, et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 2005; 33(1): 165–74

    Article  PubMed  CAS  Google Scholar 

  35. Wang H, Negishi M. Transcriptional regulation of cytochrome p450 2B genes by nuclear receptors. Curr Drug Metab 2003; 4(6): 515–25

    Article  PubMed  CAS  Google Scholar 

  36. Wang JS, Ruan Y, Taylor RM, et al. The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int J Neuropsychopharmacol 2004; 7(4): 415–9

    Article  PubMed  CAS  Google Scholar 

  37. Wang JS, Taylor R, Ruan Y, et al. Olanzapine penetration into brain is greater in transgenic Abcb1a P-glycoprotein-deficient mice than FVB1 (wild-type) animals. Neuropsychopharmacology 2004; 29(3): 551–7

    Article  PubMed  CAS  Google Scholar 

  38. Handschin C, Blattler S, Roth A, et al. The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals [online]. Nucl Recept 2004; 2(1): 7. Available from URL: http://www.nuclearreceptor.com/content/2/1/17 [Accessed 2008 Jul 1]

    Article  PubMed  Google Scholar 

  39. Chen ML, Chen CH. Microarray analysis of differentially expressed genes in rat frontal cortex under chronic risperidone treatment. Neuropsychopharmacology 2005; 30(2): 268–77

    Article  PubMed  CAS  Google Scholar 

  40. Fatemi SH, Reutiman TJ, Folsom TD, et al. Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique. Neuropsychopharmacology 2006; 31(9): 1888–99

    Article  PubMed  CAS  Google Scholar 

  41. Feher LZ, Kaiman J, Puskas LG, et al. Impact of haloperidol and risperidone on gene expression profile in the rat cortex. Neurochem Int 2005; 47(4): 271–80

    Article  PubMed  CAS  Google Scholar 

  42. Derenne JL, Baldessarini RJ. Clozapine toxicity associated with smoking cessation: case report. Am J Ther 2005; 12(5): 469–71

    Article  PubMed  Google Scholar 

  43. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs 2001; 15(6): 469–94

    Article  PubMed  CAS  Google Scholar 

  44. Gehlhaus M, Schmitt N, Volk B, et al. Antiepileptic drugs affect neuronal androgen signaling via a cytochrome P450-dependent pathway. J Pharmacol Exp Ther 2007; 322(2): 550–9

    Article  PubMed  CAS  Google Scholar 

  45. Heudorf U, Angerer J. Urinary monohydroxylated phenanthrenes and hydroxypyrene: the effects of smoking habits and changes induced by smoking on monooxygenase-mediated metabolism. Int Arch Occup Environ Health 2001; 74(3): 177–83

    Article  PubMed  CAS  Google Scholar 

  46. Jefferson JW. Complex chemical concoctions. J Clin Psychiatry 2006; 67(2): 322–3

    Article  Google Scholar 

  47. Krusekopf S, Roots I. St John’s wort and its constituent hyper-forin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways. Pharmacogenet Genomics 2005; 15(11): 817–29

    Article  PubMed  CAS  Google Scholar 

  48. Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 2001; 21(5): 500–15

    Article  PubMed  CAS  Google Scholar 

  49. Mori Y, Koide A, Kobayashi Y, et al. Effects of cigarette smoke and a heterocyclic amine, MeIQx on cytochrome P-450, mutagenic activation of various carcinogens and glucuronidation in rat liver. Mutagenesis 2003; 18(1): 87–93

    Article  PubMed  CAS  Google Scholar 

  50. Pan L, Vander SR, Rosseel MT, et al. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Ther Drug Monit 1999; 21(5): 489–97

    Article  PubMed  CAS  Google Scholar 

  51. Zullino DF, Delessert D, Eap CB, et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002; 17(3): 141–3

    Article  PubMed  CAS  Google Scholar 

  52. Wei P, Zhang J, Dowhan DH, et al. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2002; 2(2): 117–26

    Article  PubMed  CAS  Google Scholar 

  53. Beaudry G, Langlois MC, Weppe I, et al. Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain. J Neurochem 2000; 75(4): 1694–702

    Article  PubMed  CAS  Google Scholar 

  54. Chrencik JE, Orans J, Moore LB, et al. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 2005; 19(5): 1125–34

    Article  PubMed  CAS  Google Scholar 

  55. DelBello MP, Cecil KM, Adler CM, et al. Neurochemical effects of olanzapine in first-hospitalization manic adolescents: a proton magnetic resonance spectroscopy study. Neuropsychopharmacology 2006; 31(6): 1264–73

    PubMed  CAS  Google Scholar 

  56. Kontkanen O, Toronen P, Lakso M, et al. Antipsychotic drug treatment induces differential gene expression in the rat cortex. J Neurochem 2002; 83(5): 1043–53

    Article  PubMed  CAS  Google Scholar 

  57. Langlois MC, Beaudry G, Zekki H, et al. Impact of anti-psychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain. Neuroscience 2001; 106(1): 117–28

    Article  PubMed  CAS  Google Scholar 

  58. Maheux J, Ethier I, Rouillard C, et al. Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action. J Pharmacol Exp Ther 2005; 313(1): 460–73

    Article  PubMed  CAS  Google Scholar 

  59. Mu Y, Zhang J, Zhang S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyr-rhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther 2006; 316(3): 1369–77

    Article  PubMed  CAS  Google Scholar 

  60. Takahashi Y, Kumanishi T, Hayashi S. Using a DNA microarray method to examine gene expression in brain from clozapine-injected mice. Ann N Y Acad Sci 2004; 1025: 561–9

    Article  PubMed  CAS  Google Scholar 

  61. Thomas EA, George RC, Danielson PE, et al. Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol Psychiatry 2003; 8(12): 983–93, 950

    Article  PubMed  CAS  Google Scholar 

  62. Watkins RE, Maglich JM, Moore LB, et al. A crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry 2003; 42(6): 1430–8

    Article  PubMed  CAS  Google Scholar 

  63. Werme M, Ringholm A, Olson L, et al. Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine. Brain Res 2000; 863(1-2): 112–9

    Article  PubMed  CAS  Google Scholar 

  64. Zhou J, Zhai Y, Mu Y, et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 2006; 281(21): 15013–20

    Article  PubMed  CAS  Google Scholar 

  65. Aravagiri M, Yuwiler A, Marder SR. Distribution after repeated oral administration of different dose levels of risperidone and 9-hydroxy-risperidone in the brain and other tissues of rat. Psychopharmacology (Berl) 1998; 139(4): 356–63

    Article  CAS  Google Scholar 

  66. Aravagiri M, Teper Y, Marder SR. Pharmacokinetics and tissue distribution of olanzapine in rats. Biopharm Drug Dispos 1999; 20(8): 369–77

    Article  PubMed  CAS  Google Scholar 

  67. Heykants J, Huang ML, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry 1994; 55 Suppl.: 13–7

    PubMed  Google Scholar 

  68. Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998; 3(2): 123–34

    Article  PubMed  CAS  Google Scholar 

  69. Kapur S, Remington G, Zipursky RB, et al. The D2 dopamine receptor occupancy of risperidone and its relationship to extra-pyramidal symptoms: a PET study. Life Sci 1995; 57(10): L103–7

    Article  Google Scholar 

  70. Farde L, Wiesel FA, Halldin C, et al. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988; 45(1): 71–6

    Article  PubMed  CAS  Google Scholar 

  71. Medori R, Mannaert E, Gründer G. Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable. Eur Neuropsychopharmacol 2006 May; 16(4): 233–44

    Article  PubMed  CAS  Google Scholar 

  72. Borison RL, Diamond B, Pathiraja A, et al. Pharmacokinetics of risperidone in chronic schizophrenic patients. Psychopharmacol Bull 1994; 30(2): 193–7

    PubMed  CAS  Google Scholar 

  73. Mannens G, Huang ML, Meuldermans W, et al. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 1993; 21(6): 1134–41

    PubMed  CAS  Google Scholar 

  74. Kando JC, Shepski JC, Satterlee W, et al. Olanzapine: a new antipsychotic agent with efficacy in the management of schizophrenia. Ann Pharmacother 1997; 31(11): 1325–34

    PubMed  CAS  Google Scholar 

  75. Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 1996; 276(2): 658–66

    PubMed  CAS  Google Scholar 

  76. Obermeyer BD, Nyhart EH, Mattiuz EL. The disposition of olanzapine in healthy volunteers [abstract]. Pharmacol 1993; 35: 176

    Google Scholar 

  77. Bergemann N, Frick A, Parzer P, et al. Olanzapine plasma concentration, average daily dose, and interaction with comedication in schizophrenic patients. Pharmacopsychiatry 2004; 37(2): 63–8

    Article  PubMed  CAS  Google Scholar 

  78. Bergstrom RF, Callaghan JT, Cerimele BJ, et al. Pharmacokinetics of olanzapine in elderly and young [abstract]. Pharm Res 1995; 12: S358

    Google Scholar 

  79. Callaghan JT, Bergstrom RF, Ptak LR, et al. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37(3): 177–93

    Article  PubMed  CAS  Google Scholar 

  80. Weiss U, Marksteiner J, Kemmler G, et al. Effects of age and sex on olanzapine plasma concentrations. J Clin Psychopharmacol 2005; 25(6): 570–4

    Article  PubMed  CAS  Google Scholar 

  81. Carrillo JA, Herraiz AG, Ramos SI, et al. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23(2): 119–27

    Article  PubMed  CAS  Google Scholar 

  82. Kassahun K, Mattiuz E, Nyhart E Jr, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 1997; 25(1): 81–93

    PubMed  CAS  Google Scholar 

  83. Mattiuz E, Franklin R, Gillespie T, et al. Disposition and metabolism of olanzapine in mice, dogs, and rhesus monkeys. Drug Metab Dispos 1997; 25(5): 573–83

    PubMed  Google Scholar 

  84. Robertson MD, McMullin MM. Olanzapine concentrations in clinical serum and postmortem blood specimens: when does therapeutic become toxic? J Forensic Sci 2000; 45(2): 418–21

    PubMed  CAS  Google Scholar 

  85. Mauri MC, Steinhilber CP, Marino R, et al. Clinical outcome and olanzapine plasma levels in acute schizophrenia. Eur Psychiatry 2005; 20(1): 55–60

    Article  PubMed  CAS  Google Scholar 

  86. Hiemke C, Dragicevic A, Grander G, et al. Therapeutic monitoring of new antipsychotic drugs. Ther Drag Monit 2004; 26(2): 156–60

    Article  CAS  Google Scholar 

  87. Rao ML, Hiemke C, Grasmader K, et al. Olanzapine: pharmacology, pharmacokinetics and therapeutic drag monitoring [in German]. Fortschr Neurol Psychiatr 2001; 69(11): 510–7

    Article  PubMed  CAS  Google Scholar 

  88. RxMed Website. Zyprexa, 2007 [online]. Available from URL: http://www.rxmed.com [Accessed 2008 Mar 15]

  89. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 2003; 31(7): 815–32

    Article  PubMed  CAS  Google Scholar 

  90. Ring BJ, Binkley SN, Vandenbranden M, et al. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996; 41(3): 181–6

    Article  PubMed  CAS  Google Scholar 

  91. Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Washington, DC: American Psychiatric Association, 1994

  92. Aravagiri M, Marder SR, Van PT, et al. Determination of risperidone in plasma by high-performance liquid chromatography with electrochemical detection: application to therapeutic drug monitoring in schizophrenic patients. J Pharm Sci 1993; 82(5): 447–9

    Article  PubMed  CAS  Google Scholar 

  93. Xue L, Crookham SB, Diamond FX, et al. Development of a gas Chromatographic method for the determination of olanzapine in human serum, and a report of patient values [abstract]. Clin Chem 1998; 44(6): A103

    Google Scholar 

  94. Pasta David J. Parameterizing models to test the hypothesis you want: coding indicator variables and modified continuous variables. Thirtieth Annual SAS Users Group International Conference; 2005 [online]. Available from URL: http://www2.sas.com/proceedings/sugi30/212-30.pdf [Accessed 2008 Jul 1]

  95. Daniel WA, Haduch A, Wojcikowski J. Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo-possible involvement of different mechanisms. Eur Neuropsychopharmacol 2005; 15(1): 103–10

    Article  PubMed  CAS  Google Scholar 

  96. Bhalla S, Ozalp C, Fang S, et al. Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha: functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 2004; 279(43): 45139–47

    Article  PubMed  CAS  Google Scholar 

  97. Thomsen JS, Kietz S, Strom A, et al. HES-1, a novel target gene for the aryl hydrocarbon receptor. Mol Pharmacol 2004; 65(1): 165–71

    Article  PubMed  CAS  Google Scholar 

  98. Jover R, Bort R, Gomez-Lechon MJ, et al. Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. FASEB J 2002; 16(13): 1799–801

    PubMed  CAS  Google Scholar 

  99. Tucker GT, Houston JB, Huang SM. EUFEPS conference report. Optimising drug development: strategies to assess drug metabolism/transporter interaction potential. Towards a consensus. European Federation of Pharmaceutical Sciences. Eur J Pharm Sci 2001; 13(4): 417–28

    Article  PubMed  CAS  Google Scholar 

  100. Gu X, Ke S, Liu D, et al. Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem 2006; 281(26): 17882–9

    Article  PubMed  CAS  Google Scholar 

  101. Zhou C, Tabb MM, Nelson EL, et al. Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest 2006; 116(8): 2280–9

    Article  PubMed  CAS  Google Scholar 

  102. Olesen OV, Linnet K. Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication. Ther Drug Monit 1999; 21(1): 87–90

    Article  PubMed  CAS  Google Scholar 

  103. Balint BL, Nagy L. Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases. Endocr Metab Immune Disord Drug Targets 2006; 6(1): 33–43

    Article  PubMed  CAS  Google Scholar 

  104. Krasowski MD, Yasuda K, Hagey LR, et al. Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors) [online]. Nucl Recept 2005; 3: 2. Available from URL: http://www.nuclearreceptor.com/content/3//l/2 [Accessed 2008 Jul 1]

  105. Sahu VM. Mechanism of action of antipsychotics, haloperidol and olanzapine in vitro [dissertation]. Petersburg (VA): Virginia Polytech Institute and State University, 2007

  106. Ethell BT, Anderson GD, Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem Pharmacol 2003; 65(9): 1441–9

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported in part by grants from Specom Research, Fremont, CA, USA and Eli Lilly, Indianapolis, IN, USA. The authors thank Edward T. Morgan, PhD, Professor, Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia for review and comments.

For additional review and comment the authors also thank Nancy Sambol, PhD, Thuy Vu, PhD and Julie Nelson, MBA from the Center for Drug Development Science at University of California, San Francisco, CA, USA (Carl Peck, Chairman), and Celia Moreno, MD (Medical Director), Joris Wiggers, MD (Psychiatry), and Barbara Liang, PhD (Pharmacology) from San Mateo County Mental Health, San Mateo, CA, USA, as well as Patrick Willems, MD, PhD, Tom Darling, PhD, Rocky Nevin, PhD, and Bina Ain, RPH. Special thanks also to Eric Shooter, PhD, Professor Emeritus, Stanford University School of Medicine, Stanford, CA, USA. The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Psychiatry, San Mateo County Mental Health Services, San Mateo, California, USA

    John K. Darby & John Herbert

  2. DMA Corporation, Palo Alto, California, USA

    David J. Pasta

  3. School of Medicine, Department of Psychiatry, Indiana University, Indianapolis, Indiana, USA

    Michael G. Wilson

Authors
  1. John K. Darby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Pasta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael G. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Herbert
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Darby, J.K., Pasta, D.J., Wilson, M.G. et al. Long-Term Therapeutic Drug Monitoring of Risperidone and Olanzapine Identifies Altered Steady-State Pharmacokinetics. Clin. Drug Investig. 28, 553–564 (2008). https://doi.org/10.2165/00044011-200828090-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-200828090-00002

Keywords

Search

Navigation