Clinical Pharmacokinetics

, Volume 37, Issue 6, pp 435–456 | Cite as

Pharmacokinetics of Haloperidol

An Update
  • Shoji Kudo
  • Takashi Ishizaki
Review Articles Drug Disposition


Haloperidol is commonly used in the therapy of patients with acute and chronic schizophrenia. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine diphosphoglucose glucuronosyltransferase.

The greatest proportion of the intrinsic hepatic clearance of haloperidol is by glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for the metabolism of haloperidol in humans. The intrinsic clearances of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude, suggesting that the same enzyme system is responsible for the 3 reactions. Large variation in the catalytic activity was observed in the CYP-mediated reactions, whereas there appeared to be only small variations in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and an inhibitor, as well as a stimulator, of CYP2D6. Reduced haloperidol is also a substrate of CYP3A4 and inhibitor of CYP2D6.

Pharmacokinetic interactions occur between haloperidol and various drugs given concomitantly, for example, carbamazepine, phenytoin, phenobarbital, fluoxetine, fluvoxamine, nefazodone, venlafaxine, buspirone, alprazolam, rifampicin (rifampin), quinidine and carteolol. Overall, drug interaction studies have suggested that CYP3A4 is involved in the biotransformation of haloperidol in humans. Interactions of haloperidol with most drugs lead to only small changes in plasma haloperidol concentrations, suggesting that the interactions have little clinical significance. On the other hand, the coadministration of carbamazepine, phenytoin, phenobarbital, rifampicin or quinidine affects the pharmacokinetics of haloperidol to an extent that alterations in clinical consequences would be expected.

In vivo pharmacogenetic studies have indicated that the metabolism and disposition of haloperidol may be regulated by genetically determined polymorphic CYP2D6 activity. However, these findings appear to contradict those from studies in vitro with human liver microsomes and from studies of drug interactions in vivo. Interethnic and pharmacogenetic differences in haloperidol metabolism may explain these observations.


Adis International Limited Haloperidol Fluoxetine Fluvoxamine Buspirone 
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  1. 1.
    Wysowski DK, Baum C. Antipsychotic drag use in the United States, 1976–1985. Arch Gen Psychiatry 1989; 46: 929–32.PubMedCrossRefGoogle Scholar
  2. 2.
    Shader RI. Approaches to the treatment of schizophrenia. In: Shader RI, editor. Manual of psychiatric therapeutics. 2nd ed. Boston (MA): Little, Brown and Co, 1994: 311–36.Google Scholar
  3. 3.
    Lohse MJ, Müller-Oerlinghausen B. Psychopharmaka. In: Schwabe U, Paffrath D. Arzneiverordnungsreport. 1996 ed. Stuttgart: Fischer Verlag, 1996: 383–402.Google Scholar
  4. 4.
    Marketing share series 22’ 94, CNS drags. Int Pharmaceut Intell 1996 Feb; 12: 36–9.Google Scholar
  5. 5.
    Ulrich S, Wurthmann C, Brosz M, et al. The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia. Clin Pharmacokinet 1998; 34: 227–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Tsang MW, Shader RI, Greenblatt DJ. Metabolism of haloperidol: clinical implications and unanswered questions. J Clin Psychopharmacol 1994; 14: 159–62.PubMedGoogle Scholar
  7. 7.
    Reschke RW. Parenteral haloperidol for rapid control of severe, disruptive symptoms of acute schizophrenia. Dis Nerv Syst 1974; 35: 112–5.PubMedGoogle Scholar
  8. 8.
    Mason AS, Granacher RP. Basic principles of rapid neuroleptization. Dis Nerv Syst 1976; 37: 547–51.PubMedGoogle Scholar
  9. 9.
    Ayd Jr FJ. Guidelines for using short-acting intramuscular neuroleptics for rapid neuroleptization. Int Drug Ther News 1977; 12: 5–12.Google Scholar
  10. 10.
    Milton GV, Jann MW. Emergency treatment of psychotic symptoms: pharmacokinetic considerations for antipsychotic drags. Clin Pharmacokinet 1995; 28: 494–504.PubMedCrossRefGoogle Scholar
  11. 11.
    Japan Pharmaceutical Information Center. Haloperidol. In: Drags in Japan: ethical drags. Tokyo: Yakugyo Jiho Co., Ltd., 1997: 1130–2.Google Scholar
  12. 12.
    Forsman A, Öhman R. Pharmacokinetic studies on haloperidol in man. Curr Ther Res 1976; 20: 319–36.PubMedGoogle Scholar
  13. 13.
    Holley FO, Magliozzi JR, Stanski DR, et al. Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther 1983; 33: 477–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Magliozzi JR, Hollister LE. Elimination half-life and bioavailability of haloperidol in schizophrenic patients. J Clin Psychiatry 1985; 46: 20–1.PubMedGoogle Scholar
  15. 15.
    Cheng YF, Paalzow LK, Bondesson U, et al. Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacology 1987; 91: 410–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Cressman WA, Bianchine JR, Slotnick VB, et al. Plasma level profile of haloperidol in man following intramuscular administration. Eur J Clin Pharmacol 1974; 7: 99–103.PubMedCrossRefGoogle Scholar
  17. 17.
    Schaffer CB, Shahid A, Javaid JI, et al. Bioavailability of intramuscular versus oral haloperidol in schizophrenic patients. J Clin Psychopharmacol 1982; 2: 274–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Forsman A, Öhman R. Applied pharmacokinetics of haloperidol in man. Curr Ther Res 1977; 21: 396–411.Google Scholar
  19. 19.
    Midha KK, Chakraborty BS, Ganes DA, et al. Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol. J Clin Psychopharmacol 1989; 9: 98–104.PubMedCrossRefGoogle Scholar
  20. 20.
    Khot V, DeVane CL, Korpi ER, et al. The assessment and clinical implications of haloperidol acute-dose, steady-state, and withdrawal pharmacokinetics. J Clin Psychopharmacol 1993; 13: 120–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Isawa S, Murasaki M, Miura S, et al. Pharmacokinetic interaction among haloperidol, carteolol, and biperiden in healthy subjects [abstract PT07004]. 21th Collegium Internationale Neuro-Psychpharmacologicum Congress; 1998 Jun 12–16; Glasgow.Google Scholar
  22. 22.
    van Putten T, Marder SR, Mintz J, et al. Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry 1992; 149: 500–5.PubMedGoogle Scholar
  23. 23.
    Doddi S, Rifkin A, Karajgi B, et al. Blood levels of haloperidol and clinical outcome in schizophrenia. J Clin Psychopharmacol 1994; 14: 187–95.PubMedCrossRefGoogle Scholar
  24. 24.
    Lane H-Y, Lin H-N, Hwu H-G, et al. Haloperidol plasma concentrations in Taiwanese psychiatric patients. J Formos Med Assoc 1995; 94: 671–8.PubMedGoogle Scholar
  25. 25.
    Ulrich S, Neuhof S, Braun V, et al. Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder. Pharmacopsychiatry 1998; 31: 163–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Uematsu T, Matsuno H, Sato H, et al. Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair. J Pharm Sci 1992; 81: 1008–11.PubMedCrossRefGoogle Scholar
  27. 27.
    Freedberg KA, Innis RB, Creese I, et al. Antischizophrenic drags: differential plasma protein binding and therapeutic activity. Life Sci 1979; 24: 2467–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Rowell FJ, Hui SM, Fairbairn AF, et al. Total and free serum haloperidol levels in schizophrenic patients and the effect of age, thioridazine and fatty acid on haloperidol-serum protein binding in vitro. Br J Clin Pharmacol 1981; 11: 377–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Morselli PL, Bianchetti G, Dugas M. Therapeutic drug monitoring of psychotropic drugs in children. Pediatr Pharmacol 1983; 3: 149–56.Google Scholar
  30. 30.
    Tang SW, Glaister J, Davidson L, et al. Total and free plasma neuroleptic levels in schizophrenic patients. Psychiatry Res 1984; 13: 285–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Eyles DW, Stedman TJ, Pond SM. Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms. Psychopharmacology 1994; 116: 161–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Froemming JS, Francis Lam YW, Jann MW, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989; 17: 396–423.PubMedCrossRefGoogle Scholar
  33. 33.
    Korpi ER, Kleinman JE, Costakos DT, et al. Reduced haloperidol in the post-mortem brains of haloperidol-treated patients. Psychiatry Res 1984; 11: 259–69.PubMedCrossRefGoogle Scholar
  34. 34.
    Forsman A, Mårtensson E, Nyberg G, et al. A gas Chromatographic method for determining haloperidol. Naunyn Schmiedebergs Arch Pharmacol 1974; 286: 113–24.PubMedCrossRefGoogle Scholar
  35. 35.
    Forsman A, Fölsch G, Larsson M, et al. On the metabolism of haloperidol in man. Curr Ther Res 1977; 21: 606–17.Google Scholar
  36. 36.
    Pape BE. Isolation and identification of a metabolite of haloperidol. J Anal Toxicol 1981; 5: 113–7.PubMedGoogle Scholar
  37. 37.
    Forsman A, Larsson M. Metabolism of haloperidol. Curr Ther Res 1978; 24: 567–8.Google Scholar
  38. 38.
    Subramanyam B, Pond SM, Eyles DW, et al. Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol. Biochem Biophys Res Commun 1991; 181: 573–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Eyles DW, McLennan HR, Jones A, et al. Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia. Clin Pharmacol Ther 1994; 56: 512–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Oida T, Terauchi Y, Yoshida K, et al. Use of antisera in the isolation of human specific conjugates of haloperidol. Xenobiotica 1989; 19: 781–93.PubMedCrossRefGoogle Scholar
  41. 41.
    Someya T, Shibasaki M, Noguchi T, et al. Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction. J Clin Psychopharmacol 1992; 12: 169–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Midha KK, Hawes EM, Hubbard JW, et al. Interconversion between haloperidol and reduced haloperidol in humans. J Clin Psychopharmacol 1987; 7: 362–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Chakraborty BS, Hubbard JW, Hawes EM, et al. Interconversion between haloperidol and reduced haloperidol in healthy volunteers. Eur J Clin Pharmacol 1989; 37: 45–8.PubMedGoogle Scholar
  44. 44.
    Jann MW, Francis Lam YW, Chang W-H. Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients. Psychopharmacology 1990; 101: 107–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Ilett KF, Mackie AE, Gellett LB, et al. Pharmacokinetics of 14Clabeled haloperidol in man. Clin Exp Pharmacol 1978; 5: 267–8.Google Scholar
  46. 46.
    Gupta SK, Kunka RL, Metz A, et al. Effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients. J Clin Pharmacol 1995; 35: 202–7.PubMedGoogle Scholar
  47. 47.
    Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 377–90.PubMedGoogle Scholar
  48. 48.
    Nies AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and drug disposition. Clin Pharmacokinet 1976; 1: 135–55.PubMedCrossRefGoogle Scholar
  49. 49.
    Blaschke TF. Protein binding and kinetics of drugs in liver diseases. Clin Pharmacokinet 1977; 2: 32–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Björntorp P, Björkerud S, Scherstén T. Subcellular fractionation of human liver. Biochim Biophys Acta 1965; 111: 375–83.PubMedCrossRefGoogle Scholar
  51. 51.
    Soudijn W, van Wijngaarden I, Allewijn F. Distribution, excretion and metabolism of neuroleptics of the butyrophenone type. Eur J Pharmacol 1967; 1: 47–57.PubMedCrossRefGoogle Scholar
  52. 52.
    Fang J, Baker GB, Silverstone PH, et al. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol 1997; 17: 227–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Mihara K, Suzuki A, Kondo T, et al. Effects of the CYP3A4*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther 1999; 65: 291–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Pan LP, Wijnant P, De Vriendt C, et al. Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. Br J Clin Pharmacol 1997; 44: 557–64.PubMedCrossRefGoogle Scholar
  55. 55.
    Inaba T, Kovacs J. Haloperidol reductase in human and guinea pig livers. Drug Metab Dispos 1989; 17: 330–3.PubMedGoogle Scholar
  56. 56.
    Eyles DW, Pond SM. Stereospecific reduction of haloperidol in human tissues. Biochem Pharmacol 1992; 44: 867–71.PubMedCrossRefGoogle Scholar
  57. 57.
    Inaba T, Kalow W, Someya T, et al. Haloperidol reduction can be assayed in human red blood cells. Can J Physiol Pharmacol 1989; 67: 1468–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Shibasaki M, Someya T, Kato T, et al. Measurement of haloperidol reductase activity in red blood cells and reduced haloperidol/ haloperidol ratios in plasma in Oriental psychiatric patients. Prog Neuropsychopharmacol Biol Psychiatry 1990; 14: 941–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. Enzyme nomenclature 1992. San Diego (CA): Academic Press, Inc., 1992: 46.Google Scholar
  60. 60.
    Felsted RL, Bachur NR. Mammalian carbonyl reductases. Drug Metab Rev 1980; 11: 1–60.PubMedCrossRefGoogle Scholar
  61. 61.
    Wermuth B. Purification and properties of an NADPH-dependent carbonyl reductase from human brain: relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase. J Biol Chem 1981; 256: 1206–13.PubMedGoogle Scholar
  62. 62.
    Tyndale RF, Kalow W, Inaba T. Oxidation of reduced haloperidol to haloperidol: involvement of human P450HD6 (sparteine/ debrisoquine monooxygenase). Br J Clin Pharmacol 1991; 31: 655–60.PubMedCrossRefGoogle Scholar
  63. 63.
    Kudo S, Odomi M. Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation. Eur J Clin Pharmacol 1998; 54: 253–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Pan LP, De Vriendt C, Belpaire FM. Characterization of the cytochrome P450 isoenzyme(s) involved in the back oxidation and the N-dealkylation of reduced haloperidol with human liver microsomes. Fundam Clin Pharmacol 1998; 12: 307.Google Scholar
  65. 65.
    Pan LP, De Vriendt C, Belpaire FM. In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics 1998; 8: 383–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Avent KM, Riker RR, Fraser GL, et al. Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: is HPTP an intermediate? Life Sci 1997; 61: 2383–90.PubMedCrossRefGoogle Scholar
  67. 67.
    Eyles DW, Avent KM, Stedman TJ, et al. Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem. Life Sci 1997; 60: 529–34.PubMedCrossRefGoogle Scholar
  68. 68.
    Fang J, Yu PH. Effect of haloperidol and its metabolites on dopamine and noradrenaline uptake in rat brain slices. Psychopharmacology 1995; 121: 379–84.PubMedCrossRefGoogle Scholar
  69. 69.
    Fang J, Yu PH. Effects of a quaternary pyridinium metabolite of haloperidol (HP+) on the viability and catecholamine levels of cultured PC12 cells. Can J Physiol Pharmacol 1997; 75: 996–1000.PubMedGoogle Scholar
  70. 70.
    Wright AM, Bempong J, Kirby ML, et al. Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res 1998; 788: 215–22.PubMedCrossRefGoogle Scholar
  71. 71.
    Subramanyam B, Woolf T, Castagnoli Jr N. Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite. Chem Res Toxicol 1991; 4: 123–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Eyles DW, McGrath JJ, Pond SM. Formation of pyridinium species of haloperidol in human liver and brain. Psychopharmacology 1996; 125: 214–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Usuki E, Pearce R, Parkinson A, et al. Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes. Chem Res Toxicol 1996; 9: 800–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Igarashi K, Kuwano S, Sugiyama Y, et al. In vivo and in vitro studies on the transportion of a neurotoxic pyridinium metabolite derived from haloperidol and its tetrahydropyridine derivative (HPTP) into the brain tissue. International Meeting of the International Society for the Study of Xenobiotics; 1998 Oct 25–9; Cairns. ISSX Proceedings 1998; 13: 167.Google Scholar
  75. 75.
    Avent KM, McGrath JJ, Gillam EMJ. The bioactivation of haloperidol to toxic metabolites by cytochrome P450 3A4 [abstract PT06001]. 21th Collegium Internationale Neuro-Psychopharmacologicum Congress; 1998 Jul 12–16; Glasgow.Google Scholar
  76. 76.
    Avent KM, Gillam EMJ. The bioactivation of haloperidol to pyridinium metabolites by cytochrome P450 3A4. International Meeting of the International Society for the Study of Xenibiotics; 1998 Oct 25–9 Cairns. ISSX Proceedings 1998; 13: 167.Google Scholar
  77. 77.
    Castagnoli N Jr, Rimoldi JM, Bloomquist J, et al. Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes. Chem Res Toxicol 1997; 10: 924–40.PubMedCrossRefGoogle Scholar
  78. 78.
    Watkins PB. Drag metabolism by cytochrome P450 in the liver and small bowel. Gastroenterol Clin North Am 1992; 21: 511–26.PubMedGoogle Scholar
  79. 79.
    Wrighton SA, VandenBranden M, Stevens JC, et al. In vitro methods for assessing human hepatic drag metabolism: their use in drag development. Drag Metab Rev 1993; 25: 453–84.CrossRefGoogle Scholar
  80. 80.
    Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: lack of prediction by the erythromycin breath test. Drag Metab Dispos 1994; 22: 947–55.Google Scholar
  81. 81.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23.PubMedGoogle Scholar
  82. 82.
    Transon C, Lecoeur S, Leemann T, et al. Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes. Eur J Clin Pharmacol 1996; 51: 79–85.PubMedCrossRefGoogle Scholar
  83. 83.
    Watkins PB, Hamilton TA, Annesley TM, et al. The erythromycin breath test as a predictor of cyclosporine blood levels. Clin Pharmacol Ther 1990; 48: 120–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Turgeon DK, Normolle DP, Leichtman AB, et al. Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients. Clin Pharmacol Ther 1992; 52: 471–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Turgeon DK, Leichtman AB, Lown KS, et al. P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients. Clin Pharmacol Ther 1994; 56: 253–60.PubMedCrossRefGoogle Scholar
  86. 86.
    Thummel KE, Shen DD, Podoll TD, et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther 1994; 271: 549–56.PubMedGoogle Scholar
  87. 87.
    Lown KS, Thummel KE, Benedict PE, et al. The erythromycin breath test predicts the clearance of midazolam. Clin Pharmacol Ther 1995; 57: 16–24.PubMedCrossRefGoogle Scholar
  88. 88.
    Inaba T, Jurima M, Mahon WA, et al. In vitro inhibition studies of two isozymes of human liver cytochrome P-450: mephenytoin p-hydroxylase and sparteine monooxygenase. Drag Metab Dispos 1985; 13: 443–8.Google Scholar
  89. 89.
    Dayer P, Desmeules J, Striberni R. In vitro forecasting of drugs that may interfere with codeine bioactivation. Eur J Drag Metab Pharmacokinet 1992; 17: 115–20.CrossRefGoogle Scholar
  90. 90.
    Kudo S, Uchida M, Odomi M. Metabolism of carteolol by cDNA-expressed human cytochrome P450. Eur J Clin Pharmacol 1997; 52: 479–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Guengerich FP, Müller-Enoch D, Blair IA. Oxidation of quinidine by human liver cytochrome P-450. Mol Pharmacol 1986; 30: 287–95.PubMedGoogle Scholar
  92. 92.
    Douyon R, Angrist B, Peselow E, et al. Neuroleptic augmentation with alprazolam: clinical effects and pharmacokinetic correlates. Am J Psychiatry 1989; 146: 231–4.PubMedGoogle Scholar
  93. 93.
    Jann MW, Ereshefsky L, Saklad SR, et al. Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol 1985; 5: 106–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Kidron R, Averbuch I, Klein E, et al. Carbamazepine-induced reduction of blood levels of haloperidol in chronic schizophrenia. Biol Psychiatry 1985; 20: 219–22.PubMedCrossRefGoogle Scholar
  95. 95.
    Arana GW, Goff DC, Friedman H, et al. Does carbamazepineinduced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry 1986; 143: 650–1.PubMedGoogle Scholar
  96. 96.
    Fast DK, Jones BD, Kusalic M, et al. Effect of carbamazepine on neuroleptic plasma levels and efficacy. Am J Psychiatry 1986; 143: 117–8.PubMedGoogle Scholar
  97. 97.
    Jann MW, Fidone GS, Hernandez JM, et al. Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation. Psychiatry Res 1989; 28: 153–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching carbamazepine to oxcarbazepine on the plasma levels of neuroleptics: a case report. Psychopharmacology 1994; 116: 115–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Isawa S, Murasaki M, Miura S, et al. Pharmacokinetic and pharmacodynamic interactions among haloperidol, carteolol hydrochloride and biperiden hydrochloride. Jpn J Neuropsychopharmacol 1999; 19: 111–8.Google Scholar
  100. 100.
    Syvälahti EKG, Taiminen T, Saarijärvi S, et al. Citalopram causes no significant alterations in plasma neuroleptic levels in schizophrenic patients. J Int Med Res 1997; 25: 24–32.PubMedGoogle Scholar
  101. 101.
    Goff DC, Midha KK, Brotman AW, et al. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine. Am J Psychiatry 1991; 148; 790–2.PubMedGoogle Scholar
  102. 102.
    Viala A, Aymard N, Leyris A, et al. Pharmacoclinical correlations in depressed schizophrenic patients treated by haloperidol decanoate and fluoxetine. Thérapie 1996; 51: 19–25.PubMedGoogle Scholar
  103. 103.
    Goff DC, Midha KK, Sarid-Segal O, et al. A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology 1995; 117: 417–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Avenoso A, Spina E, Campo G, et al. Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications. Pharmacol Res 1997; 35: 335–9.PubMedGoogle Scholar
  105. 105.
    Daniel DG, Randolph C, Jaskiw G, et al. Coadministration of fluvoxamine increases serum concentrations of haloperidol. J Clin Psychopharmacol 1994; 14: 340–3.PubMedCrossRefGoogle Scholar
  106. 106.
    Vandel S, Bertschy G, Baumann P, et al. Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients. Pharmacol Res 1995; 31: 347–53.PubMedCrossRefGoogle Scholar
  107. 107.
    Yasui N, Kondo T, Otani K, et al. Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism. J Clin Psychopharmacol 1999; 19: 149–54.PubMedCrossRefGoogle Scholar
  108. 108.
    Stevens A, Stevens I, Mahal A, et al. Haloperidol and lorazepam combined: clinical effects and drug plasma levels in the treatment of acute schizophrenic psychosis. Pharmacopsychiatry 1992; 25: 273–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Barbhaiya RH, Shukla UA, Greene DS, et al. Investigation of pharmacokinetic and pharmacodynamic interactions after coadministration of nefazodone and haloperidol. J Clin Psychopharmacol 1996; 16: 26–34.PubMedCrossRefGoogle Scholar
  110. 110.
    Linnoila M, Viukari M, Vaisanen K, et al. Effect of anticonvulsants on plasma haloperidol and thioridazine levels. Am J Psychiatry 1980; 137: 819–21.PubMedGoogle Scholar
  111. 111.
    Greendyke RM, Kanter DR. Plasma propranolol levels and their effect on plasma thioridazine and haloperidol concentrations. J Clin Psychopharmacol 1987; 7: 178–82.PubMedCrossRefGoogle Scholar
  112. 112.
    Greendyke RM, Gulya A. Effect of pindolol administration on serum levels of thioridazine, haloperidol, phenytoin, and phenobarbital. J Clin Psychiatry 1988; 49: 105–7.PubMedGoogle Scholar
  113. 113.
    Young D, Midha KK, Fossler MJ, et al. Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6. Eur J Clin Pharmacol 1993; 44: 433–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Takeda M, Nishinuma K, Yamashita S, et al. Serum haloperidol levels of schizophrenics receiving treatment for tuberculosis. Clin Neuropharmacol 1986; 9: 386–97.PubMedCrossRefGoogle Scholar
  115. 115.
    Lee MS, Kim YK, Lee SK, et al. A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia. J Clin Psychopharmacol 1998; 18: 399–403.PubMedCrossRefGoogle Scholar
  116. 116.
    Ishizaki T, Chiba K, Saito M, et al. The effects of neuroleptics (haloperidol and chlorpromazine) on the pharmacokinetics of valproic acid in schizophrenic patients. J Clin Psychopharmacol 1984; 4: 254–61.PubMedCrossRefGoogle Scholar
  117. 117.
    Physician’s Desk Reference. 52 ed. Montvale (NJ): Medical Economics Company, Inc., 1998: 3037–41.Google Scholar
  118. 118.
    Hesslinger B, Norman C, Langosch JM, et al. Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychpharmacol 1999; 19: 310–5.CrossRefGoogle Scholar
  119. 119.
    Ged C, Rouillon JM, Pichard L, et al. The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450III A induction. Br J Clin Pharmacol 1989; 28: 373–87.PubMedCrossRefGoogle Scholar
  120. 120.
    Pirmohamed M, Allott R, Green VJ, et al. Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy. Br J Clin Pharmacol 1994; 37: 577–81.PubMedCrossRefGoogle Scholar
  121. 121.
    Pirmohamed M, Kitteringham NR, Park BK. The role of active metabolites in drug toxicity. Drug Saf 1994; 11: 114–44.PubMedCrossRefGoogle Scholar
  122. 122.
    Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet 1996; 31: 198–214.PubMedCrossRefGoogle Scholar
  123. 123.
    Lele P, Peterson P, Yang S, et al. Cyclosporine and Tegretol®: another drug interaction. Kidney Int 1985; 27: 344.Google Scholar
  124. 124.
    Hillebrand G, Castro LA, van Scheidt W, et al. Valproate for epilepsy in renal transplant recipients receiving cyclosporine. Transplantation 1987; 43: 915–6.PubMedGoogle Scholar
  125. 125.
    Alvarez JS, Del Castillo JAS, Ortiz MJA. Effect of carbamazepine on cyclosporin blood level. Nephron 1991; 58: 235–6.CrossRefGoogle Scholar
  126. 126.
    Backman JT, Olkkola KT, Ojala M, et al. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 1996; 37: 253–7.PubMedCrossRefGoogle Scholar
  127. 127.
    Rapport DJ, Calabrese JR. Interactions between carbamazepine and birth control pills. Psychosomatics 1989; 30: 462–4.PubMedCrossRefGoogle Scholar
  128. 128.
    Back DJ, Grimmer SFM, L’e Orme M, et al. Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics. Br J Clin Pharmacol 1988; 25: 527–32.PubMedCrossRefGoogle Scholar
  129. 129.
    Crawford P, Chadwick DJ, Martin C, et al. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990; 30: 892–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Greene DS, Barbhaiya RH. Clinical pharmacokinetics of nefazodone. Clin Pharmacokinet 1997; 33: 260–75.PubMedCrossRefGoogle Scholar
  131. 131.
    Glue P, Banfield CR, Perhach JL, et al. Pharmacokinetic interactions with felbamate: In vitro-in vivo correlation. Clin Pharmacokinet 1997; 33: 214–24.PubMedCrossRefGoogle Scholar
  132. 132.
    Bertilsson L, Tybring G, Widén J, et al. Carbamazepine treatment inducers the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol 1997; 44: 186–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Levy RH, Rettenmeier AW, Anderson GD, et al. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 1990; 48: 225–35.PubMedCrossRefGoogle Scholar
  134. 134.
    Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet 1993; 25: 433–43.PubMedCrossRefGoogle Scholar
  135. 135.
    Binnie CD, van Emde Boas W, Kasteleijn-Nolste-Trenite DGA, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 1986; 27: 248–54.PubMedCrossRefGoogle Scholar
  136. 136.
    Jawad S, Yuen WC, Peck AW, et al. Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res 1987; 1: 194–201.PubMedCrossRefGoogle Scholar
  137. 137.
    Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400.PubMedCrossRefGoogle Scholar
  138. 138.
    Park BK, Kitteringham NR, Pirmohamed M, et al. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41: 477–91.PubMedCrossRefGoogle Scholar
  139. 139.
    Jerling M, Lindström L, Bondesson U, et al. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16: 368–74.PubMedCrossRefGoogle Scholar
  140. 140.
    Yue Q-Y, Tomson T, Säwe J. Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man. Pharmacogenetics 1994; 4: 193–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Perucca E, Richens A. Biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 31–50.Google Scholar
  142. 142.
    Guengerich FP. Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 1988; 33: 500–8.PubMedGoogle Scholar
  143. 143.
    Back DJ, L’e Orme M. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18: 472–84.PubMedCrossRefGoogle Scholar
  144. 144.
    Maggs JL, Park BK. A comparative study of biliary and urinary 2-hydroxylated metabolites of [6,7-3H] 17α-ethynylestradiol in woman. Contraception 1985; 32: 173–82.PubMedCrossRefGoogle Scholar
  145. 145.
    Back DJ, L’e Orme M. Drug interactions. In: Goldzieher JW, editor. Pharmacology of the contraceptive steroids. New York: Raven Press, 1994: 407–25.Google Scholar
  146. 146.
    Pichard L, Fabre I, Fabre G, et al. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990; 18: 595–606.PubMedGoogle Scholar
  147. 147.
    Riva R, Albani F, Contin M, et al. Pharmacokinetic interactions between antiepileptic drugs. Clin Pharmacokinet 1996; 31: 470–93.PubMedCrossRefGoogle Scholar
  148. 148.
    Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clin Pharmacokinet 1996; 31: 444–69.PubMedCrossRefGoogle Scholar
  149. 149.
    Brosen K, Skjelbo E. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6: the source of the sparteine/debrisoquine oxidation polymorphism. Br J Clin Pharmacol 1991; 32: 136–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Crewe HK, Lennard MS, Tucker GT, et al. The effect of selective serotonin re-uptake inhibitors on cytochrome P450 2D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5.PubMedCrossRefGoogle Scholar
  151. 151.
    Otton SV, Wu D, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Schmider J, Greenblatt DJ, von Moltke LL, et al. N-Demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors. J Pharmacol Exp Ther 1995; 275: 592–7.PubMedGoogle Scholar
  153. 153.
    Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 1994; 14: 90–8.PubMedGoogle Scholar
  154. 154.
    Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992; 51: 239–48.PubMedCrossRefGoogle Scholar
  155. 155.
    El-Yazigi A, Chaleby K, Gad A, et al. Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone. J Clin Pharmacol 1995; 35: 17–21.PubMedGoogle Scholar
  156. 156.
    Lemberger L, Rowe H, Bosomworth JC, et al. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1988; 43: 412–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Lasher TA, Fleishaker JC, Steenwyk RC, et al. Pharmacokinetic-pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology 1991; 104: 323–7.PubMedCrossRefGoogle Scholar
  158. 158.
    Greenblatt DJ, Preskorn SH, Cotreau MM, et al. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther 1992; 52: 479–86.PubMedCrossRefGoogle Scholar
  159. 159.
    Grimsley SR, Jann MW, Gary Carter J, et al. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Phannacol Ther 1991; 50: 10–5.CrossRefGoogle Scholar
  160. 160.
    Wright CE, Lasher-Sisson TA, Steenwyk RC, et al. A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine. Pharmacotherapy 1992; 12: 103–6.PubMedGoogle Scholar
  161. 161.
    Greenblatt DJ, von Moltke LL, Schmider J, et al. Inhibition of human cytochrome P450-3A isoforms by fluoxetine and norfluoxetine: in vitro and in vivo studies. J Clin Pharmacol 1996; 36: 792–8.PubMedGoogle Scholar
  162. 162.
    Brosen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45: 1211–4.PubMedCrossRefGoogle Scholar
  163. 163.
    Buur Rasmussen B, Nielsen TL, Brosen K. Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol 1998; 54: 735–40.CrossRefGoogle Scholar
  164. 164.
    Skjelbo E, Brøsen K. Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Phannacol 1992; 34: 256–61.CrossRefGoogle Scholar
  165. 165.
    von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125–31.CrossRefGoogle Scholar
  166. 166.
    Rasmussen BB, Mäenpää J, Pelkonen O, et al. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Phannacol 1995; 39: 151–9.CrossRefGoogle Scholar
  167. 167.
    Sperber AD. Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy. Drug Saf 1991; 6: 460–2.PubMedCrossRefGoogle Scholar
  168. 168.
    Diot P, Jonville AP, Gerard F, et al. Possible interaction between theophylline and fluvoxamine. Therapie 1991; 46: 170–1.PubMedGoogle Scholar
  169. 169.
    Jeppesen U, Loft S, Poulsen HE, et al. A fluvoxamine-caffeine interaction study. Pharmacogenetics 1996; 6: 213–22.PubMedCrossRefGoogle Scholar
  170. 170.
    Spina E, Campo GM, Avenoso A, et al. Interaction between fluvoxamine and imipramine/desipramine in four patients. Ther Drug Monit 1992; 14: 194–6.PubMedCrossRefGoogle Scholar
  171. 171.
    Bertschy G, Vandel S, Vandel B, et al. Fluvoxamine-tricyclic antidepressant interaction. An accidental finding. Eur J Clin Pharmacol 1991; 40: 119–20.PubMedCrossRefGoogle Scholar
  172. 172.
    Hiemke C, Weigmann H, Härtter S, et al. Elevated levels of clozapine in serum after addition of fluvoxamine. J Clin Psychopharmacol 1994; 14: 279–81.PubMedCrossRefGoogle Scholar
  173. 173.
    Jeppesen U, Gram LF, Vistisen K, et al. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51: 73–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Xu Z-H, Xie H-G, Zhou H-H. In vivo inhibition of CYP2C19 but not CYP2D6 by fluvoxamine. Br J Clin Phannacol 1996; 42: 518–21.CrossRefGoogle Scholar
  175. 175.
    Jeppesen U, Buur Rasmussen B, Brøsen K. Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide. Clin Phannacol Ther 1997; 62: 279–86.CrossRefGoogle Scholar
  176. 176.
    Spina E, Pollicino AM, Avenoso A, et al. Effect of fluvoxamine on the phannacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 1993; 15: 243–6.PubMedCrossRefGoogle Scholar
  177. 177.
    Bonnet P, Vandel S, Nezelof S, et al. Carbamazepine, fluvoxamine: is there a pharmacokinetic interaction? Therapie 1992; 47: 165.PubMedGoogle Scholar
  178. 178.
    Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583–4.PubMedCrossRefGoogle Scholar
  179. 179.
    Fleishaker JC, Hulst LK. A phannacokinetic and phannacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–9.PubMedCrossRefGoogle Scholar
  180. 180.
    Perucca E, Gatti G, Cipolla G, et al. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. Clin Pharmacol Ther 1994; 56: 471–6.PubMedCrossRefGoogle Scholar
  181. 181.
    Lamberg TS, Kivistö KT, Laitila J, et al. The effect of fluvoxamine on the pharmacokinetics and phannacodynamics of buspirone. Eur J Clin Pharmacol 1998; 54: 761–6.PubMedCrossRefGoogle Scholar
  182. 182.
    Schmider J, Greenblatt DJ, von Moltke LL, et al. Inhibition of cytochrome P450 by nefazodone in vitro: studies of dextromethorphan O- and N-demethylation. Br J Clin Pharmacol 1996; 41: 339–43.PubMedCrossRefGoogle Scholar
  183. 183.
    von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransfonnation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Phannacol Exp Ther 1996; 276: 370–9.Google Scholar
  184. 184.
    Kroboth PD, Folan MM, Lush RM, et al. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment. J Clin Psychophannacol 1995; 15: 306–19.CrossRefGoogle Scholar
  185. 185.
    Barbhaiya RH, Shukla UA, Kroboth PD, et al. Coadministration of nefazodone and benzodiazepines: II. A phannacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995; 15: 320–6.PubMedCrossRefGoogle Scholar
  186. 186.
    Greene DS, Salazar DE, Dockens RC, et al. Coadministration of nefazodone and benzodiazepine: III. A phannacokinetic interaction study with alprazolam. J Clin Psychophannacol 1995; 15: 399–408.CrossRefGoogle Scholar
  187. 187.
    Helms-Smith KM, Curtis SL, Hatton RC. Apparent interaction between nefazodone and cyclosporine. Ann Intern Med 1996; 125: 424.PubMedGoogle Scholar
  188. 188.
    Ashton AK, Wolin RE. Nefazodone-induced carbamazepine toxicity. Am J Psychiatry 1996; 153: 733.PubMedGoogle Scholar
  189. 189.
    Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Phannacol 1996; 41: 149–56.CrossRefGoogle Scholar
  190. 190.
    Goff DC, Midha KK, Brotman AW, et al. An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychophannacol 1991; 11: 193–7.Google Scholar
  191. 191.
    Jajoo HK, Mayol RF, LaBudde JA, et al. Metabolism of the antianxiety drug buspirone in human subjects. Drug Metab Dispos 1989; 17: 634–40.PubMedGoogle Scholar
  192. 192.
    Jajoo HK, Blair IA, Klunk LJ, et al. In vitro metabolism of the antianxiety drug buspirone as a predictor of its metabolism in vivo. Xenobiotica 1990; 20: 779–86.PubMedCrossRefGoogle Scholar
  193. 193.
    Mayol RF, Adamson DS, Gammans RE, et al. Pharmacokinetics and disposition of 14C-buspirone HC1 after intravenous and oral dosing in man. Clin Phannacol Ther 1985; 37: 210.Google Scholar
  194. 194.
    Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 1986; 32: 114–29.PubMedCrossRefGoogle Scholar
  195. 195.
    Kivistö KT, Lamberg TS, Kantola T, et al. Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Clin Phannacol Ther 1997; 62: 348–54.CrossRefGoogle Scholar
  196. 196.
    Lamberg TS, Kivistö KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther 1998; 63: 640–5.PubMedCrossRefGoogle Scholar
  197. 197.
    Greenblatt DJ, von Molfke LL, Harmatz JS, et al. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry 1993; 54 Suppl.: 4–11.PubMedGoogle Scholar
  198. 198.
    Venkatakrishnan K, Greenblatt DJ, von Moltke LL, et al. Alprazolam is another substrate for human cytochrome P450-3A isoforms [abstract]. J Clin Psychopharmacol 1998; 18: 256.PubMedCrossRefGoogle Scholar
  199. 199.
    Furukori H, Otani K, Yasui N, et al. Effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam. Neuropsychopharmacology 1998; 18: 364–9.PubMedCrossRefGoogle Scholar
  200. 200.
    Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions. Arch Intern Med 1992; 152: 711–6.PubMedCrossRefGoogle Scholar
  201. 201.
    Parkinson A. Biotransformation of xenobiotics. In: Klaassen CD, editor. Casarett and Doull’s Toxicology, the basic science of poisons. 5th ed. New York: McGraw-Hill, 1996: 113–86.Google Scholar
  202. 202.
    Otton SV, Inaba T, Kalow W. Competitive inhibition of sparteine oxidation in human liver by β-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 1984; 34: 73–80.PubMedCrossRefGoogle Scholar
  203. 203.
    Edwards DJ, Bellevue FH, Woster PM. Identification of 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996; 24: 1287–90.PubMedGoogle Scholar
  204. 204.
    Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents: decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 1997; 25: 1228–33.PubMedGoogle Scholar
  205. 205.
    Hashimoto K, Shirafuji T, Sekino H, et al. Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects. Eur J Clin Pharmacol 1998; 54: 753–60.PubMedCrossRefGoogle Scholar
  206. 206.
    Bailey DG, Malcolm BJ, Arnold O, et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10.PubMedCrossRefGoogle Scholar
  207. 207.
    Yasui N, Kondo T, Suzuki A, et al. Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice. Int Clin Psychopharmacol 1999; 14: 133–8.CrossRefGoogle Scholar
  208. 208.
    Eagling VA, Profit L, Back DJ. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol 1999; 48: 543–52.PubMedCrossRefGoogle Scholar
  209. 209.
    Shimoda K, Someya T, Morita S, et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999; 21: 293–6.PubMedCrossRefGoogle Scholar
  210. 210.
    Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 1979; 9: 221–8.PubMedCrossRefGoogle Scholar
  211. 211.
    Dawson GW, Vestal RE. Smoking and drug metabolism. Pharmacol Ther 1982; 15: 207–21.CrossRefGoogle Scholar
  212. 212.
    Miller LG. Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics. Clin Pharmacokinet 1989; 17: 90–108.PubMedCrossRefGoogle Scholar
  213. 213.
    Perry PJ, Miller DD, Arndt SV, et al. Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics. J Clin Psychopharmacol 1993; 13: 46–51.PubMedCrossRefGoogle Scholar
  214. 214.
    Bertilsson L, Dahl M-L. Polymorphic drug oxidation: relevance to the treatment of psychiatric disorders. CNS Drugs 1996; 5: 200–23.CrossRefGoogle Scholar
  215. 215.
    Spina E, Ancione M, Di Rosa AE, et al. Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects. Eur J Clin Pharmacol 1992; 42: 347–8.PubMedCrossRefGoogle Scholar
  216. 216.
    Gram LF, Debruyne D, Caillard V, et al. Substantial rise in sparteine metabolic ratio during haloperidol treatment. Br J Clin Pharmacol 1989; 27: 272–5.PubMedCrossRefGoogle Scholar
  217. 217.
    Llerena A, Alm C, Dahl M-L, et al. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther Drug Monit 1992; 14: 92–7.PubMedCrossRefGoogle Scholar
  218. 218.
    Llerena A, Dahl M-L, Ekqvist B, et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther Drug Monit 1992; 14: 261–4.PubMedCrossRefGoogle Scholar
  219. 219.
    Lane H-Y, Yoa-Pu Hu O, Jann MW, et al. Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients. Psychiatry Res 1997; 69: 105–11.PubMedCrossRefGoogle Scholar
  220. 220.
    Nyberg S, Farde L, Halldin C, et al. D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152: 173–8.PubMedGoogle Scholar
  221. 221.
    Suzuki A, Otani K, Mihara K, et al. Effects of the CYP2D6 genotype on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese schizophrenic patients. Pharmacogenetics 1997; 7: 415–8.PubMedCrossRefGoogle Scholar
  222. 222.
    Potkin SG, Shen Y, Pardes H, et al. Haloperidol concentrations elevated in Chinese patients. Psychiatry Res 1984; 12: 167–72.PubMedCrossRefGoogle Scholar
  223. 223.
    Jann MW, Chang W-H, Davis CM, et al. Haloperidol and reduced haloperidol plasma levels in Chinese vs. non-Chinese psychiatric patients. Psychiatry Res 1989; 30: 45–52.PubMedCrossRefGoogle Scholar
  224. 224.
    Someya T, Takahashi S, Shibasaki M, et al. Reduced haloperidol/haloperidol ratios in plasma: polymorphism in Japanese psychiatric patients. Psychiatry Res 1990; 31: 111–20.PubMedCrossRefGoogle Scholar
  225. 225.
    Chang W-H, Chen T-Y, Lee C-F, et al. Low plasma reduced haloperidol/haloperidol ratios in Chinese patients. Biol Psychiatry 1987; 22: 1406–8.PubMedCrossRefGoogle Scholar
  226. 226.
    Lam YWF, Jann MW, Chang W-H, et al. Intra- and interethnic variability in reduced haloperidol to haloperidol ratios. J Clin Pharmacol 1995; 35: 128–36.PubMedGoogle Scholar
  227. 227.
    Bertilsson L, Lou Y-Q, Du Y-L, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97.PubMedCrossRefGoogle Scholar
  228. 228.
    Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402–8.PubMedCrossRefGoogle Scholar
  229. 229.
    Sohn D-R, Shin S-G, Park C-W, et al. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 1991; 32: 504–7.PubMedCrossRefGoogle Scholar
  230. 230.
    Horai Y, Nakano M, Ishizaki T, et al. Metroprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198–207.PubMedCrossRefGoogle Scholar
  231. 231.
    Alván G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Shoji Kudo
    • 1
  • Takashi Ishizaki
    • 2
  1. 1.Tokushima Research InstituteOtsuka Pharmaceutical Co., LtdTokushimaJapan
  2. 2.Department of Pharmacology and Therapeutics, Graduate School of Clinical PharmacyKumamoto UniversityKumamotoJapan

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