Abstract
1. Antipsychotic drugs are extensively metabolised by cytochrome P450 (CYP) enzymes.
2. Dispositions of a number of antipsychotic drugs have been shown to cosegregate with polymorphism of CYP2D6.
3. Metabolic drug–drug interactions have frequently been observed when antipsychotics are coadministered with other drugs.
4. Many antipsychotic drugs are converted to active metabolites which can contribute to the therapeutic or side effects of the parent drug.
5. Information concerning the individual CYP isoenzymes involved in the metabolism of antipsychotic drugs is important for the safe clinical use of this group of drugs.
Similar content being viewed by others
REFERENCES
Alvarez-Mena, S. C., and Frank, M. J. (1973). Phenothiazine-induced T-wave abnormalities. Effects of overnight fasting. JAMA 224:1730–1733.
Alvir, J. M., Lieberman, J. A., Safferman, A. Z., Schwimmer, J. L., and Schaaf, J. A. (1993). Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N. Engl. J. Med. 329:162–167.
Arana, G. W., Goff, D. C., Friedman, H., Ornsteen, M., Greenblatt, D. J., Black, B., and Shader, R. I. (1985). Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am. J. Psychiatry 143:650–651.
Arita, M., and Mashiba, H. (1970). Effects of phenothiazine and propranolol on ECG. The effects of propranolol on the electrocardiographic abnormalities induced by phenothiazine derivatives. Jpn. Circ. J. 34:391–400.
Axelsson, R. (1977). On the serum concentrations and antipsychotic effects of thioridazine, thioridazine side-chain sulfoxide and thioridazine side-chain sulfone. Curr. Ther. Res. 21:587–605.
Axelsson, R., and Mårtensson, E. (1977). The concentration pattern of nonconjugated thioridazine metabolites in serum by thioridazine treatment and its relationship to physiological and clinical variables. Curr. Ther. Res. 20:561–586.
Baker, G. B., Coutts, R. T., and Holt, A. (1994). Metabolism and chirality in psychopharmacology. Biol. Psychiatry 36:211–213.
Bertilsson, L., Carrillo, J. A., Dahl, M. L., Llerena, A., Alm, C., Bondesson, U., Lindstrom, L., Rodriguez de la Rubia, I., Ramos, S., and Benitez, J. (1994). Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br. J. Clin. Pharmacol. 38:471–473.
Bertz, R. J., and Grannerman, G. R. (1997). Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin. Pharmacokinet. 32:210–258.
Blake, B. L, Rose. R. L., Mailman, R. B., Levi, P. E., and Hodgson, E, (1995). Metabolism of thioridazine by microsomal monooxygenases: Relative roles of P450 and flavin-containing monooxygenase. Xenobiotica 25: 377–393.
Bloomquist, J., King, E., Wright, A., Mytilineou, C., Kimura, K., Castagnoli, K., and Castagnoli, N., Jr. (1994). 1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies. J. Pharmacol. Exp. Ther. 270:822–830.
Bolvig Hansen, L., and Larsen, N. E. (1977). Plasma concentrations of perphenazine and its sulphoxide metabolite during continuous oral treatment. Psychopharmacology 53:127–130.
Bolvig Hansen, L., Elley, J., Rosted Christensen, T., Larsen, N. E., Naestoft, J., and Hvidberg, E. F. (1979). Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergic drugs. Br. J. Clin. Pharmacol. 7:75–80.
Bolvig Hansen, L., Larsen, N. E., and Vestergård, P. (1981). Plasma levels of perphenazine (Trilafon) related to development of extrapyramidal side effects. Psychopharmacology 74:306–309.
Bouchard, R. H., Pourcher, E., and Vincent, P. (1989). Fluoxetine and extrapyramidal side effects. Am. J. Psychiatry 146:1352–1353.
Britto, M. R., and Wedlund, P. J. (1992). Cytochrome P-450 in the brain. Potential evolutionary and therapeutic relevance of localization of drug-metabolizing enzymes. Drug Metab. Dispos. 20:446–450.
Byerley, M. J., and DeVane, L. (1996). Pharmacokinetics of clozapine and risperidone: A review of recent literature. J. Clin. Psychopharmcol. 16:177–187.
Casey, D. E. (1995). Tardive dyskinesia. In Bloom, F. E., and Kupfer, D. J. (eds.) Psychopharmacology: The Fourth Generation of Progress, Raven Press, New York, pp. 1497–1502.
Centorrino, F., Baldessarini, R. J., Kando, J., Frankenburg, F. R., Volpicelli, S. A., Puopolo, P. R., and Flood, J. G. (1994). Serum concentrations of clozapine and its major metabolites: Effects of cotreatment with fluoxetine or valproate. Am. J. Psychiatry 151:123–125.
Cheng, Y. F., Lundberg, T., Bondesson, U., Lindstrom, L., and Gabrielsson, J. (1988). Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur. J. Clin. Pharmacol. 34:445–449.
Choc, M. G., Lehr, R. G., Hsuan, F., Honigfeld, G., Smith, H. T., Borison, R., and Volavka, J. (1987). Multiple-dose pharmacokinetics of clozapine in patients. Pharma. Res. 4:402–405.
Choc, M. G., Hsuan, F., Honigfeld, G., Robinson, W. T., Ereshefsky, L., Crismon, M. L., Saklad, S. R., Hirschowitz, J., and Wagner, R. (1990). Single-vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharma. Res. 7:347–351.
Cholerton, S., Daly, A. K., and Idle, J. R. (1992). The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol. Sci. 13:434–439.
Cohen, B. M., Lipinski, J. F., and Waternaux, C. (1989). A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites. Psychopharmacology 97:481–488.
Cooper, T. B. (1978). Plasma level monitoring of antipsychotic drugs. Clin. Pharmacokinet. 3:14–38.
Coutts, R. T. (1994). Polymorphism in the metabolism of drugs, including antidepressant drugs: Comments on phenotyping. J. Psychiatr. Neurosci. 19:30–44.
Dahl, M. L., Ekqvist, B., Widen, J., and Bertilsson, L. (1991). Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr. Scand. 84:99–102.
Dahl, M. L., Llerena, A., Bondesson, U., Lindström, L., and Bertilsson, L. (1994). Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br. J. Clin. Pharmacol. 37:71–74.
Dahl, S. G. (1982). Active metabolites of neuroleptic drugs: possible contribution to therapeutic and toxic effects. Ther. Drug Monit. 4:33–40.
Dahl-Puustinen, M. L., Liden, A., Alm, C., and Bertilsson, L. (1989). Disposition of perphenazine is related to polymorphic debrisoquine hydroxylation in man. Clin. Pharmacol. Ther. 46:78–81.
Daniel, D. G., Randolph, C., Jaskiw, G., Handel, S., Williams, T., Abi-Dargham, A., Shoaf, S., Egan, M., Elkashef, A., Liboff, S., and Linnoila, M. (1994). Coadministration of fluvoxamine increases serum concentrations of haloperidol. J. Clin. Psychopharmacol. 14:340–343.
de Mol, N. J., and Busker, R. W. (1984). Irreversible binding of the chlorpromazine radical cation and of photoactivated chlorpromazine to biological macromolecules. Chem.-Biol. Interact. 52:79–92.
de Mol, N. J., Becht, A. B. C., Koenen, J., and Lodder, G. (1986). Irreversible binding with biological macromolecules and effects in bacterial mutagenicity tests of the radical cation of promethazine and photoactivated promethazine. Comparison with chlorpromazine. Chem.-Biol. Interact. 57:73–83.
Derenne, F., Joanne, C., Vandel, S., Bertschy, G., Volmat, R., and Bechtel, P. (1989). Debrisoquine oxidative phenotyping and psychiatric drug treatment. Eur. J. Clin. Pharmacol. 36:53–58.
Dom, R. (1967). Local glial reaction in the CNS of albino-rats in response to the administration of a neuroleptic drug (Butyrophenone). Acta Neurol. Belg. 67:755–762.
Edge, S. C., Markowitz, J. S., and DeVane, C. L. (1997). Clozapine drug-drug interactions: A review of the literature. Hum. Psychopharmacol. 12:5–20.
Eiermann, B., Engel, G., Johansson, I., Zanger, U. M., and Bertilsson, L. (1997). The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br. J. Clin. Pharmacol. 44:439–446.
Eyles, D. W., McLennan. H. R., Jones, A., McGrath, J. J., Stedman, T. J., and Pond, S. M. (1994). Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia. Clin. Pharmacol. Ther. 56:512–520.
Fang, J. (1997). Amphetamine-like behavioural effects induced by perinigral injection of the pyridinium metabolite of haloperidol in rat. Can. J. Physiol. Pharmacol. 74:1359–1361.
Fang, J., and Gorrod, J. W. (1991). Dehydration is the first step in the biotransformation of haloperidol to its pyridinium metabolite. Toxicol. Lett. 59:117–123.
Fang, J., and Gorrod, J. W. (1993). An HPLC system for the analysis of haloperidol and seven of its metabolites in microsomal preparations. J. Chromatogr. 614:267–273.
Fang, J., and Yu, P. H., (1995). Effects of haloperidol and its metabolites on dopamine and noradrenaline uptake in rat brain preparations. Psychopharmacology 121:379–384.
Fang, J., Gorrod, J. W., Kajbaf, M., Lamb, J. H., and Nalyor, S. (1993). Investigation of the neuroleptic drug haloperidol and its metabolites using tandem mass spectro. Int. J. Mass Spectrometry Ion Process. 22:121–131.
Fang, J., Zuo, D. M., and Yu, P. H. (1995a). A comparison of a quaternary pyridinium metabolite of haloperidol (HP+) with the neurotoxin N-methyl-4-phenylpyridinium (MPP+) towards cultured dopaminergic neuroblastoma cells. Psychopharmacology 121:373–378.
Fang, J., Yu, P. H., Gorrod, J. W., and Boulton, A. A. (1995b). Inhibition of monoamine oxidase by haloperidol and its metabolites: Pharmacological implications for the chemotherapy of schizophrenia. Psychopharmacology 118:206–212.
Fang, J., Lai, C. T., and Yu, P. H. (1996a). Neurotoxic effects of 4-(4-chlorophenyl-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), a major metabolite of haloperidol, on dopaminergic systems in vitro and in vivo. Biogen. Amines 12:125–134.
Fang, J., Coutts, R. T., McKenna, K. F., and Baker, G. B. (1998). Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn-Schmiedeberg's Arch. Pharmacol. 358:592–599.
Fang, J., Baker, G. B., and Coutts, R. T. (1996c). Determination of 4-chlorophenyl-4-hydroxypiperidine, a metabolite of haloperidol, by gas chromatography with electron-capture detection. J. Chromatogr. Biomed. Appl. 682:283–288.
Fang, J., Baker, G. B., Silverstone, P. H., and Coutts, R. T. (1997). Involvement of CYP3A4 and CYP2D6 in a number of major metabolic pathways of haloperidol. Cell Mol. Neurobiol. 17:227–233.
Fischer, V., Vogels, B., Maurer, G., and Tynes, R. E. (1992). The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J. Pharmacol. Exp. Ther. 260:1355–60.
Fonne-Pfister, R., and Meyer, U. A. (1988). Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, and target of the debrisoquine/sparteine type polymorphism. Biochem. Pharmacol. 37:3829–3835.
Forrest, I. S., and Green, D. E. (1972). Phenothiazines: metabolism and analytical detection. J. Forens. Sci. 17:592–617.
Forrest, F. M., Forrest, I. S., and Serra, M. T. (1970). Modification of chlorpromazine metabolism by some other drugs frequently administered to psychiatric patients. Biol. Psychiatry 2:53–58.
Forsman, A., and Larsson, M. (1978). Metabolism of haloperidol. Curr. Ther. Res. 24:567–568.
Gaedigk, A., Blum, M., Gaedigk, R., Eichelbaum, M., and Meyer, U. A. (1991). Deletion of the entire cytrochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am. J. Hum. Genet. 48:943–950.
Gagneux, A. R. (1976). The chemistry of cabamazepine. In Birkmayer, B. (ed.), Epileptic Seizures-Behavior-Pain, Hans Huber, Berne, pp. 120–126.
Gauch, R., and Michaelis, W. (1971). The metabolism of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine (clozapine) in mice, dogs and human subjects. Farmaco Ed. Pratica 26:667–681.
Gerson, S. L., Arce, C., and Meltzer, H. Y. (1994). N-Desmethylclozapine: A clozapine metabolite that suppresses haemopoiesis. Br. J. Haematol. 86:555–561.
Glazer, W. M., Moore, D. C., Schooler, N. R., Brenner, L. M., and Morgenstern, H. (1984). Tardive dyskinesia: A discontinuation study. Arch. Gen. Psychiatry 41:623–627.
Glue, P., and Banfield, C. (1996). Psychiatry, psychopharmacology and P-450s. Hum. Psychopharmacol. 11:97–114.
Goff, D. C., Brotman, A. W., Waites, M., and McCormick, S. (1990). Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients. Am. J. Psychiatry 147:492–494.
Goff, D. C., Midha, K. K., Brotman, A. W., Waites, M., and Baldessarini, R. J. (1991). Elevation of plasma concentrations of haloperidol after the addition of fluoxetine. Am. J. Psychiatry 148:790–794.
Gorrod, J. W., and Fang, J. (1993). On the metabolism of haloperidol. Xenobiotica 23:495–508.
Gram, L. F., and Fredricson Overø, K. (1972). Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. Br. Med. J. 1:463–465.
Gram, L. F., Debruyne, D., Caillard, V., Boulenger, J. P., Lacotte, J., Moulin, M., and Zarifian, E. (1989). Substantial rise in sparteine metabolic ratio during haloperidol treatment. Br. J. Clin. Pharmacol. 27:272–275.
Greenblatt, D. J., Gross, P. L., Harris, J., Shader R. I. and Ciraulo, D. A. (1978). Fatal hyperthermia following haloperidol therapy of sedative-hypnotic withdrawal. J. Clin. Psychiatry 39:673–675.
Hale, P. W., and Poklis, A. (1986). Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine 5-sulfoxide in the isolated perfused rat heart. Toxicol. Appl. Pharmacol. 86:44–55.
Hansson, T., Tindberg, N., Ingelman-Sundberg, M., and Köhler, C. (1990). Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34:451–463.
Haring, C., Meise, U., Humpel, C., Saria, A., Fleischhacker, W. W., and Hinterhuber, H. (1989). Dose-related plasma levels of clozapine: Influence of smoking behaviour, sex and age. Psychopharmacology 99(Suppl.):38–40.
Hasegawa, M., Gutierrez-Esteinou, R., Way, L., and Meltzer, H. (1993). Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: Effect of smoking. J. Clin. Psychopharmacol. 13:383–390.
He, H., and Richardson, J. S. (1995). A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 receptors. Int. Clin. Psychopharmacol. 10:19–30.
Hedlund, E., Wyss, A., Kainu, T., Backlund, M., Köhler C., Pelto-Huikko, M., Gustafsson, J.-Å., and Warner, M. (1996). Cytochrome P4502D4 in the brain: Specific neuronal regulation by clozapine and toluene. Mol. Pharmacol. 50:342–350.
Heykants, J., Huang, M. L., Mannens, G., Meuldermans, W., Snoeck, E., Van Beijsterveldt, L., Van Peer, A., and Woestenborghs, R. (1994). The pharmacokinetics of risperidone in humans: A summary. J. Clin. Psychiatry. 55(Suppl.):13–17.
Hiemke, C., Weigmann, H., Hartter, S., Dahmen, N., Wetzel, H., and Muller, H. (1994). Elevated levels of clozapine in serum after addition of fluvoxamine. J. Clin. Psychopharmacol. 14:279–81.
Howes, C. A., Pullar, T., Sourindhrin, I., Mistra, P. C., Capel, H., Lawson, D. H., and Tilstone, W. J. (1983). Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine. Eur. J. Clin. Pharmacol. 24:99–102.
Hubbard, J. W., Midha, K. K., Hawes, E. M., McKay, G., Marder, S. R., Aravagiri, M., and Korchinski, E. D. (1993). Metabolism of phenothiazine and butyrophenone antipsychotic drugs: A review of some recent research findings and clinical implications. Br. J. Psychiatry 163:19–24.
Inaba, T., and Kovacs, J. (1989). Haloperidol reductase in human and guinea pig livers. Drug Metab. Dispos. 17:330–333.
Inaba, T., Jurima, M., Mahon, W. A., and Kalow, W. (1985). In vitro inhibition of human liver cytochrome P450. Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab. Dispos. 13:443–448.
Jann, M. W., Ereshefsky, L., Saklad, S. R., Seidel, D. R., Davis, C. M., Burch, N. R., and Bowden, C. L. (1985). Effects of carbamazepine on plasma haloperidol levels. J. Clin. Psychopharmacol. 5:106–109.
Jann, M. W., Saklad, S. R., Ereshefsky, L. O., Richards, A. L., Harrington, C. A., and Davis, C. M. (1986). Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology 90:468–470.
Jann, M. W., Fidone, G. S., Hernandez, J. M., Amrung, S., and Davis, C. M. (1989). Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation. Psychiatry Res. 28:153–159.
Jerling, M., Lindstrom, L., Bondesson, U., and Bertilsson, L. (1994). Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther. Drug Monit. 16:368–374.
Kallio, J., Huupponen, R., Seppala, M., Sako, E. and Iisalo, E. (1990). The effect of beta-adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine. Br. J. Clin. Pharmacol. 30:638–643.
Kane, J., Honigfeld, G., Singer, J., Meltzer, H. Y., Clozaril® Collaborative Study Group (1988). Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45:789–796.
Kelder, P. P., Fischer, M. J. E., de Mol, N. J., and Janssen, L. H. M. (1991). Oxidation of chlorproazine by methemoglobin in the presence of hydrogen peroxide. Formation of chlorpromazine radical cation and its covalent binding to methemoglobin. Arch. Biochem. Biophys. 284:313–319.
Kempermann, G., Knoth, R., Gebiicke-Haerter, P. J., Stolz, B. J., and Volk, B. (1994). Cytochrome P450 in rat astrocytes in vivo and in vitro: Intracellular localization and induction by phenytoin. J. Neurosci. Res. 39:576–588.
Kidron, R., Averbuch, I., Klein, E., and Belmaker, R. H. (1985). Carbamazepine induced reduction of blood levels of haloperidol in chronic schizophrenia. Biol. Psychiatry 20:219–222.
Klein, E., Bental, E., Lerer, B., and Belmaker, R. H. (1984). Combination of carbamazepine and haloperidol versus placebo and haloperidol in excited psychoses: A controlled study. Arch. Gen. Psychiatry 41:165–170.
Koizumi, J., and Shiraishi, H. (1973). Synaptic changes in the rabbit pallidum following long-term haloperidol adminstration. Folia Psychiatr. Neurol. Jpn. 27:51–57.
Korpi, E. R., Costakos, D. T., and Wyatt, R. J. (1985). Interconversions of haloperidol and reduced haloperidol in guinea pig and rat liver microsomes. Biochem. Pharmacol. 34:2923–2927.
Kragh-Sørensen, P., Borgå, O, Garle, M., Bolvig Hansen, L., Hansen, C. E., Hvidberg, E. F., Larsen, N. E., and Sjoqvist, F. (1977). Effect of simultaneous treatment with low doses of perphenazine on plasma and urine concentrations of nortriptyline and 10-hydroxynortriptyline. Eur. J. Clin. Pharmacol. 11:479–483.
Krupp, P., and Barnes, P. (1989). Leponex-associated granulocytopenia: A review of the situation. Psychopharmacology 99 (Suppl.):118–21.
Lewi, P. J., Heykants, J. J. P., Allewijn, F. T. N., Dony, J. G. H., and Janssen, P. A. J. (1970). Distribution and metabolism of neuroleptic drugs, part 1: Pharmacokinetics of haloperidol. Arzneimittelforschung 20:943–948.
Liccione, J. J., and Maines, M. D. (1989). Manganese-mediated increase in rat brain mitochondrial cytochrome P-450 and drug metabolism activity—Susceptibility of the striatum. J. Pharmacol. Exp. Ther. 248:222–228.
Lin, G., Hawes E. M., McKay, G., Korchinski, E. D., and Midha, K. K., (1993). Metabolism of piperidine-type phenothiazine antipsychotic agents. IV. Thioridazine in dog, man and rat. Xenobiotica 23:1059–1074.
Linnet, K., and Oleson, O. V. (1997). Metabolism of clozapine by cDNA expressed human cytochrome P450 enzymes. Drug Metab. Dispos. 25:1379–1382.
Linnoila, M., Viukari, M., Vaisanen, K., and Auvinen, J. (1980). Effect of anticonvulsants on plasma haloperidol and thioridazine levels. Am. J. Psychiatry 137:819–821.
Llerena, A., Alm, C., Dahl, M. L, Ekqvist, B., and Bertilsson, L. (1992). Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther. Drug Monit. 14:92–97.
Llerena, A., Herraíz, A. G., Cobaleda, J., Johansson, I., and Dahl, M. L. (1993). Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents. Clin. Pharmacol. Ther. 54:606–611.
Mannens, G., Huang, M. L., Meuldermans, W., Hendrickx, J., Woestenborghs, R., and Heykants, J. (1993). Absorption, metabolism, and excretion of risperidone in humans. Drug Metab. Dispo. 21:1134–1141.
Megens, A. A., Awouters, F. H., Schotte, A., Meert, T. F., Dugovic, C., Niemegeers, C. J., and Leysen, J. E. (1994) Survey on the pharmacodynamics of the new antipsychotic risperidone. Psychopharmacology 114:9–23.
Meltzer, H. Y., Cola, P., Way, L., Thompson, P. A., Bastani, B., Davies, M. A., and Snitz, B. (1993). Cost effectiveness of clozapine in neuroleptic-resistant schizophrenia. Am. J. Psychiatry 150:1630–1638.
Meshul, C. K., and Casey, D. E. (1989). Regional, reversible ultrastructural changes in rat brain with chronic neuroleptic treatment. Brain Res. 489:338–346.
Meshul, C. K., Andreassen, O. A., Allen, C., and Jorgensen, H. A. (1996). Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol. Psychopharmacology 125:238–247.
Meuldermans, W., Hendricks, J., Mannens, G., Lavrijsen, K., Janssen, C., Bracke, J., Le Jeune, L., Lauwers, W., and Heykants, J. (1994). The metabolism and excretion of risperidone after oral administration in rats and dogs. Drug Metab. Dispo. 22:129–138.
Meyer, G. W., Woggon, B., Baumann, P., and Meyer, U. A. (1990). Clinical implications of slow sulphoxidation of thioridazine in a poor metabolizer of the debrisoquine type. Eur. J. Clin. Pharmacol. 39:613–614.
Midha, K. K., Chakraborty, B. S., Ganes, D. A., Hawes, E. M., Hubbard, J. W., Keegan, D. L., Korchinski, E. D., and McKay, G. (1989). Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol. J. Clin. Psychopharmacol. 9:98–104.
Midha, K. K., Hawes, E. M., Hubbard, J. W., Korchinski, E. D., and McKay, G. (1987). Interconversion between haloperidol and reduced haloperidol in humans. J. Clin. Psychopharmacol. 7:362–364.
Miller, D. D., Kelly, M. W., Perry, P. J., and Coryell, W. H., (1990). The influence of cigarette smoking on haloperidol pharmacokinetics. Biol. Psychiatry 28:529–531.
Muusze, R. G., and Huber, J. F. K. (1974). Determination of the psychotropic drug thioridazine and its metabolites in blood by means of high pressure liquid chromatography in combination with fluorometric reaction detection. J. Chromatog. Sci. 12:779–787.
Nelson, D. R., Kamataki, T., Waxman, D. J., Guengerich, F. L., Estabrook, R. W., Feyereisen, R., Gonzalez, F. J., Coon, M. J., Gunsalus, I. C., Gotoh, O., Okuda, K., and Nebert, D. W. (1993). The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12:1–51.
Nelson, J. C., and Jatlow, P. I. (1980). Neuroleptic effect on desipramine steady-state plasma concentrations. Am. J. Psychiatry 137:1232–1234.
Öhman, R., Larsson, M., Nilsson, I. M., Engel, J., and Carlsson, A. (1977). Neurometabolic and behavioural effects of haloperidol in relation to drug levels in serum and brain. Naunyn-Schmiedeberg Arch. Pharmacol. 299:105–114.
Okey, A. B. (1990). Enzyme induction in the cytochrome P-450 system. Pharmacol. Ther. 45:241–298.
Olianas, M., De Montis, G. M., Concu, A., Tagliamonte, A., and Di Chiara, G. (1978). Intranigral kainic acid: Evidence for nigral non-dopaminergic neurons controlling posture and behavior in manner opposite to the dopaminergic ones. Eur. J. Pharmacol. 49:223–232.
Ozdemir, V., Naranjo, C. A., Herrmann, N., Reed, K., Sellers, E. M., and Kalow, W. (1997). Paroxetine potentiates the central nervous system side effects of perphenazine: Contribution of cytochrome P4502D6 inhibition in vivo. Clin. Pharmacol. Ther. 62:334–347.
Pan, L. P., Wijnant, P., DeVriendt, C., Rosseel, M. T., and Belpaire, F. M. (1997). Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. Br. J. Clin. Pharmacol. 44:557–564.
Pantuck, E. J., Pantuck, C. B., Anderson, K. E., Conney, A. H., and Kappas, A. (1982). Cigarette smoking and chlorpromazine disposition and actions. Clin. Pharmacol. Ther. 31:533–538.
Papadopoulos, A. S., and Crammer, J. L., (1986). Suphoxide metabolites of thioridazine in man. Xenobiotica 16:1097–1107.
Papadopoulos, A. S., Crammer, J. L., and Cowan, D. A. (1985). Phenolic metabolites of thioridazine in man. Xenobiotica 15:309–316.
Peet, M., Middlemiss, D. N., and Yates, R. A. (1981). Propranolol in schizophrenia. II. Clinical and biochemical aspects of combining propranolol with chlorpromazine. Br. J. Psychiatry 139:112–117.
Perrin, R., Minn, A., Ghersi-Egea, J. F., Grassiot, M, C., and Seist, G., (1990). Distribution of cytochrome P450 activities towards alkoxyresorufin derivatives in rat brain regions, subcellular fractions and isolated cerebral microvessels. Biochem. Pharmacol. 40:2145–2151.
Piette, L. H., Bulow, G., and Yamazaki, J. (1964). Electron-paramagnetic-resonance studies of the chlorpromazine free radical formed during enzymatic oxidation by peroxidase-hydrogen peroxide. Biochim. Biophys. Acta 88:120–129.
Pirmohamed, M., Williams, D., Madden, S., Templeton, E., and Park, B. K. (1995). Metabolism and bioactivation of clozapine by human liver in vitro. J. Pharmacol. Exp. Ther. 272:984–990.
Raitasuo, V., Lehtovaara, R., and Huttunen, M. O. (1993). Carbamazepine and plasma levels of clozapine. Am. J. Psychiatry 150:169.
Ring, B. J., Catlow, J., Lindsay, T. J., Gillespie, T., Roskos, L. K., Cerimele, B. J., Swanson, S. P., Hamman, M. A., and Wrighton, S. A., (1996). Identification of the human cytochrome P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J. Pharmacol. Exp. Ther. 276:658–666.
Rollema, H., Skolnik, M., d'Engelbronner, J., Igarashi, K., Usuki, E., and Castagnoli, N., Jr. (1994). MPP+-like neurotoxicity of a pyridinium metabolite derived from haloperidol: In vivo microdialysis and in vitro mitochondrial studies. J. Pharmacol. Exp. Ther. 268:380–387.
Schilter, B., and Omiecinski, C. J. (1993). Regional distribution and expression modulation of cytochrome P-450 and epoxide hydrolase mRNAs in the rat brain. Mol. Pharmacol. 44:990–996.
Seeman, P. (1988). Tardive dyskinesia, dopamine receptors, and neuroleptic damage to cell membranes. J. Clin. Psychopharmacol. 8 (Suppl.):3–9.
Shen, W. W. (1995). Cytochrome P450 monooxygenases and interactions of psychotropic drugs: A five-year update. Int. J. Psychiatry Medi. 25:277–290.
Shen, W. W. (1997). The metabolism of psychoactive drugs: A review of enzymatic biotransformation and inhibition. Biol Psychiatry 41:814–826.
Soudijn, W., Van Wijngaarden, I., and Allewijn, F. (1967). Distribution, excretion and metabolism of neuroleptics of the butyrophenone type: part I. Excretion and metabolism of haloperidol and nine related butyrophenone-derivatives in the Wistar rat. Eur. J. Pharmacol. 1:47–57.
Spina, E., Birgersson, C., von Bahr, C., Ericsson, O., Mellstrom, B., Steiner, E., and Sjoqvist, F. (1984). Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin. Pharmacol. Ther. 36:677–682.
Spina, E., Martines, C., Caputi, A. P., Cobaleda, J., Pinas, B., Carrillo, J. A., and Benitez, J. (1991). Debrisoquine oxidation phenotype during neuroleptic monotherapy. Eur. J. Clin. Pharmacol. 41:467–470.
Spina, E., Ancione, M., Di Rosa, A. E., Meduri, M., and Caputi, A. P. (1992a). Polymorphic debrisoquine oxidation and acute neuroleptic induced adverse effects. Eur. J. Clin. Pharmacol. 42:347–348.
Spina, E., Sturiale, V., Valvo, S., Ancione, M., Di Rose, A. E., Meduri, M., and Caputi, A. P. (1992b). Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions. Acta Psychiatr. Scand. 86:364–366.
Spina, E., Campo, G. M., Calandra, S., Caputi, A. P., Carrillo, J. A., and Benitez, J. (1992c). Debrisoquine oxidation in an Italian population: A study in healthy subjects and in schizophrenic patients. Pharmacol. Res. 25:43–50.
Sproule, B. A., Naranjo, C. A., Bremner, K. E., and Hassan, P. C. (1997). Selective serotonin reuptake inhibitors and CNS drug interactions: A critical review of the evidence. Clin. Pharmacokinet. 33:454–471.
Stimmel, G. L., and Falloon, I. R. (1983). Chlorpromazine plasma levels, adverse effects, and tobacco smoking: Case report. J. Clin. Psychiatry 44:420–422
Subramanyam, B., Rollema, H., Woolf, T., and Castagnoli, N., Jr. (1990). Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats. Biochem. Biophys. Res. Commun. 166:238–244.
Swett, C. Jr., (1974). Drowsiness due to chlorpromazine in relation to cigarette smoking. Arch. Gen. Psychiatry 31:211–214.
Swett, C. Jr., Cole, J. O., Hartz, S. C., Shapiro, S., and Slone, D. (1977). Hypotension due to chlorpromazine. Relation to cigarette smoking, blood pressure, and dosage. Arch. Gen. Psychiatry 34:661–663.
Syvälahti, E. K. G., Lindberg, R., Kallio, J., and de Vocht, M. (1986). Inhibitiory effecs of neuroleptics on debrisoquine oxidation in man. Br. J. Clin. Pharmacol. 22:89–92.
Tate, J. L. (1989). Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. Am. J. Psychiatry 146:399–400.
Tugnait, M., Hawes, E. M., McKay, G., Eichelbaum, M., and Midha, K. K. (1999). Characterization of the human hepatic cytochromes P450 involved in the in vitro oxidation of clozapine. Chem. Biol. Interact. 118:171–189.
Tugnait, M., Hawes, E. M., McKay, G., Rettie, A. E., Haining, R. L., and Midha, K. K. (1997). N-oxidation of clozapine by flavin-containing monooxygenase. Drug Metab. Dispos. 25:524–527.
Turano, P., Turner, W. J., and Manian, A. A. (1973). Thin-layer chromatography of chlorpromazine metabolites. J. Chromatogr. 75:277–293.
Tyndale, R. F., Sunahara, R., Inaba, T., Kalow, W., Gonzalez, F. J., and Niznik, H. B. (1991). Neuronal cytochrome debrisoquine/sparteine-type oxidation: Potent inhibition of activity by (−)-cocaine and sequence identity to hepatic cytochrome P450 CYP2D6. Mol. Pharmacol. 40:63–68.
Tyson, S. C., Devane, C. L., and Risch, S. C. (1995). Pharmacokinetic interaction between risperidone and clozapine. Am. J. Psychiatry 152:1401–1402.
Van Beijsterveldt, L. E., Geerts, R. J., Leysen, J. E., Megens, A. A., Van den Eynde, H. M., Meuldermans, W. E., and Heykants, J. J. (1994). Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology 114:53–62.
Vanderheeren, F. A. J., and Muusze, R. G. (1977). Plasma levels and half lives of thioridazine and some of its metabolites. Eur. J. Clin. Pharmacol. 11:135–140.
Van der Schyf, C. J., Castagnoli, K., Usuki, E., Fouda, H. G., Rimoldi, J. M., and Castagnoli, N., Jr. (1994). Metabolic studies on haloperidol and its tetrahydropyridine analog in C57BL/6 mice. Chem. Res. Tox. 7:281–285.
Volk, B., Hettmannsperger, U., Papp, Th., Amellizad, Z., Oesch, F., and Knoth, R. (1988). First evidence of cytochrome P-450 induction in the mouse brain by phenytoin. Neurosci. Lett. 84:219–224.
Volk, B., Hettmannsperger, U., Papp, Th., Amelizad, Z., Oesch, F., and Knoth, R. (1991). Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. Neuroscience 42:215–235.
Volpicelli, S. A., Centorrino, F., Puopolo, P. R., Kando, J., Frankenburg, F. R., Baldessarini, R. J., and Flood, J. G. (1993). Determination of clozapine, norclozapine, and clozapine-N-oxide in serum by liquid chromatography. Clin. Chem. 39:1656–1659.
von Bahr, C., Movin, G., Nordin, C., Lidén, A., Hammarlund-Udenaes, M., Hedberg, A., Ring, H., and Sjöqvist, F. (1991). Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin. Pharmacol. Ther. 49:234–240.
von Bahr, C., Spina, E., Birgersson, C., Ericsson, Ö., Goransson, M., Henthorn, T., and Sjöqvist, F. (1985). Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem. Pharmacol. 34:2501–2505.
Warner, M., and Gustafssen, J. A. (1994). Effect of ethanol on cytochrome P450 in the rat brain. Proc. Natl. Acad. Sci. USA 91:1019–1023.
Warner, M., Köhler, C., Hansson, T., and Gustafsson, J. A. (1988). Regional distribution of cytochrome P-450 in the rat brain: Spectral quantitation and contribution of P-450b, e and P-450c, d. J. Neurochem. 50:1057–1065.
Wetzel, H., Anghelescu, I., Szegedi, A., Wiesner, J., Weigmann, H., Hartter, S., and Hiemke, C. (1998). Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: Differential effects of fluvoxamine and paroxetine in a prospective study. J. Clin. Psychopharmacol. 18:2–9.
Young, D., Midha, K. K., Fossler, M. J., Hawes, E. M., Hubbard, J. W., McKay, G., and Korchinski, E. D. (1993). 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. 44:433–438.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fang, J., Gorrod, J.W. Metabolism, Pharmacogenetics, and Metabolic Drug–Drug Interactions of Antipsychotic Drugs. Cell Mol Neurobiol 19, 491–510 (1999). https://doi.org/10.1023/A:1006938908284
Issue Date:
DOI: https://doi.org/10.1023/A:1006938908284