Human CYP2D6 and metabolism of m-chlorophenylpiperazine

  • Susan Rotzinger
    Neurochemical Research Unit, Department of Psychiatry and Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada
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  • Jian Fang
    Neurochemical Research Unit, Department of Psychiatry and Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada
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  • Ronald T Coutts
    Neurochemical Research Unit, Department of Psychiatry and Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada
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  • Glen B Baker
    Address reprint requests to Dr. G.B. Baker, Neurochemical Research Unit, Department of Psychiatry, 1E7.44 W Mackenzie Health Sciences Centre, University of Alberta, Edmonton, AB, T6G 2B7, Canada
    Neurochemical Research Unit, Department of Psychiatry and Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada
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      Background: Metabolic drug–drug interactions can occur between drugs that are substrates or inhibitors of the same cytochrome P450 (CYP) isoenzymes, but can be prevented by knowing which isoenzymes are primarily responsible for a drug’s metabolism. m-Chlorophenylpiperazine (mCPP) is a psychopharmacologically active metabolite of four different psychiatric drugs. The present experiments were designed to identify the CYP isoenzymes involved in the metabolism of mCPP to its main metabolite p-hydroxy-mCPP (OH-mCPP).
      Methods: The rate of production of OH-mCPP from mCPP was correlated with isoform activities in a panel of human liver microsomes, was assessed using a panel of individual complementary DNA-expressed human CYP isoenzymes, and was investigated in the presence of a specific inhibitor of CYP2D6.
      Results: OH-mCPP production correlated significantly with CYP2D6 activity in human liver microsomes. Furthermore, incubations with microsomes from cells expressing CYP2D6 resulted in OH-mCPP formation, whereas no mCPP was formed from incubations with microsomes from cells expressing other individual isoforms. Finally, when the specific CYP2D6 inhibitor quinidine was preincubated with either human liver microsomes or cells expressing human CYP2D6, there was a concentration-dependent decrease in the production of OH-mCPP.
      Conclusions: These results confirm that CYP2D6 is the isoform responsible for the p-hydroxylation of mCPP, and indicate that caution should be exercised in coprescribing inhibitors or substrates of CYP2D6 with drugs that have mCPP as a metabolite.


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        • Barbhaiya R.H
        • Buch A.B
        • Greene D.S
        Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan.
        Br J Clin Pharmacol. 1996; 42: 573-581
        • Bertz R.J
        • Granneman G.R
        Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions.
        Clin Pharmacokinet. 1997; 32: 210-258
        • Birkett D.J
        • Mackenzie P.I
        • Veronese M.E
        • Miners J.O
        In vitro approaches can predict human drug metabolism.
        Trends Pharmacol Sci. 1993; 14: 292-294
        • Bourrie M
        • Meunier V
        • Berger Y
        • Fabre G
        Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes.
        J Pharmacol Exp Ther. 1996; 277: 321-332
        • Brosen K
        • Gram L.F
        Clinical significance of the sparteine/debrisoquine oxidation polymorphism.
        Eur J Clin Pharmacol. 1989; 36: 537-547
        • Buch A.B
        • Shukla U.A
        • Pittman K
        • Barbhaiya R.H
        Pharmacokinetics of nefazodone in extensive and poor metabolizers of dextromethorphan.
        Pharm Res. 1993; 10: S314
        • Caccia S
        • Ballabio M
        • Samanin R
        • Zanini M.G
        • Garattini S
        (−)-m-Chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone.
        J Pharm Pharmacol. 1981; 33: 477-478
        • Cholerton S
        • Daly A.K
        • Idle J.R
        The role of individual human cytochromes P450 in drug metabolism and clinical response.
        Trends Pharmacol Sci. 1992; 13: 434-439
        • Conn J.P
        • Sanders-Bush E
        Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT-2 and 5-HT-1C) receptors.
        J Pharmacol Exp Ther. 1987; 242: 552-557
        • Coutts R.T
        • Bach M.V
        • Baker G.B
        Metabolism of amitriptyline with CYP2D6 expressed in a human cell line.
        Xenobiotica. 1997; 27: 33-47
        • Cowen P.J
        • Sargent P.A
        • Williams C
        • Goodall E.M
        • Orlikov A.B
        Hypophagic, endocrine and subjective responses to m-chlorophenylpiperazine in healthy men and women.
        Hum Psychopharmacol. 1995; 10: 385-391
        • Ellingrod V.L
        • Perry P.J
        Am J Health Syst Pharm. 1995; 52: 2799-2812
        • Ereshefsky L
        • Riesenman C
        • Lam Y.M.F
        Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6.
        Clin Pharmacokinet. 1995; 29: 10-19
        • Fang J
        • Baker G.B
        • Silverstone P.H
        • Coutts R.T
        Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol.
        Cell Mol Neurobiol. 1997; 17: 227-233
        • Fiorella D
        • Rabin R.A
        • Winter J.C
        The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of m-chlorophenylpiperazine.
        Psychopharmacology. 1995; 119: 222-230
        • Fong M.H
        • Garattini S
        • Caccia S
        1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone, and mepiprazole.
        J Pharm Pharmacol. 1982; 34: 674-675
        • Germine M
        • Goddard A.W
        • Sholomskas D.E
        • Woods S.W
        • Charney D.S
        • Heninger G.R
        Response to meta-chlorophenylpiperazine in panic disorder patients and healthy subjects.
        Psychiatry Res. 1994; 54: 115-133
        • Gibson E.L
        • Barnfield A.M.C
        • Curzon G
        Evidence that mCPP-induced anxiety in the plus-maze is mediated by postsynaptic 5-HT(2C) receptors but not by sympathomimetic effects.
        Neuropharmacology. 1994; 33: 3-4
        • Guengerich F.P
        In vitro techniques for studying drug metabolism.
        J Pharmacokinet Biopharmaceut. 1997; 24: 521-533
        • Ishida M
        • Otani K
        • Kaneko S
        • Ohkubo T
        • Osanai T
        • Yasui N
        • et al.
        Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine.
        Int Clin Psychopharmacol. 1995; 10: 143-146
        • Kahn R.S
        • Wetzler S
        m-Chlorophenylpiperazine as a probe of serotonin function.
        Biol Psychiatry. 1991; 30: 1139-1166
        • Kahn R.S
        • Asnis G.M
        • Wetzler S
        • van Praag H.M
        Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder.
        Psychopharmacology. 1988; 96: 360-364
        • Kahn R.S
        • Wetzler S
        • Asnis G.M
        • Kling M.A
        • Suckow R.F
        • van Praag H.M
        Effects of m-chlorophenylpiperazine in normal subjects.
        Psychopharmacology. 1990; 100: 339-344
        • Kalus O
        • Wetzler S
        • Kahn R.S
        • Asnis G.M
        • van Praag H.M
        A dose-response study of intravenous m-chlorophenylpiperazine in normal subjects.
        Psychopharmacology. 1992; 106: 388-390
        • Kaul S
        • Shukla U.A
        • Barbhaiya R.H
        Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses.
        J Clin Pharmacol. 1995; 35: 830-839
        • Kobayashi K
        • Chiba K
        • Yagi T
        • Shimada N
        • Taniguchi T
        • Horie T
        • et al.
        Identification of cytochrome p450 isoforms involved in citalopram N-demethylation by human liver microsomes.
        J Pharmacol Exp Ther. 1997; 280: 927-933
        • Krystal J.H
        • Seibyl J.P
        • Price L.H
        • Woods S.W
        • Heninger G.R
        • Aghajanian G.K
        • et al.
        m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients.
        Arch Gen Psychiatry. 1993; 50: 624-635
        • Lemoine A
        • Gautier J.C
        • Azoulay D
        • Kiffel L
        • Belloc C
        • Guengerich F.P
        • et al.
        Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver.
        Mol Pharmacol. 1993; 43: 827-832
        • Manchee G.R
        • Eddershaw P.J
        • Ranshaw L.E
        • Herriott D
        • Park G.R
        • Bayliss M.K
        • et al.
        The aliphatic oxidation of salmeterol to α-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.
        Drug Metab Dispos Biol Fate Chem. 1996; 24: 555-559
        • Market G.J
        • McDougle C.J
        • Price L.H
        • Seiden L.S
        A comparison of trazodone and fluoxetine.
        Psychopharmacology. 1992; 109: 2-11
        • Mayol R.F
        • Cole C.A
        • Colson K.E
        • Kerns E.H
        Isolation and identification of the major urinary metabolite of m-chlorophenylpiperazine in the rat.
        Drug Metab Dispos Biol Fate Chem. 1994; 22: 171-174
        • Mayol R.F
        • Cole C.A
        • Luke G.M
        • Colson K.L
        • Kerns E.H
        Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma.
        Drug Metab Dispos Biol Fate Chem. 1994; 22: 304-311
        • Melzacka M
        • Boksa J
        • Maj J
        J Pharm Pharmacol. 1979; 31: 855-856
        • Mueller E.A
        • Murphy D.L
        • Sunderland T
        Further studies of the putative serotonin agonist, m-chlorophenylpiperazine.
        Psychopharmacology. 1986; 89: 388-391
        • Muralidharan G
        • Hawes E.M
        • McKay G
        • Korchinski E.D
        • Midha K.K
        Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.
        Eur J Clin Pharmacol. 1991; 41: 471-474
        • Murphy D.L
        • Mueller E.A
        • Hill J.L
        • Tolliver T.J
        • Jacobsen F.M
        Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers.
        Psychopharmacology. 1989; 98: 275-282
        • Nakajima M
        • Yamamoto T
        • Nunoya K.-I
        • Yokoi T
        • Nagashima K
        • Inoue K
        • et al.
        Characterization of CYP2A6 involved in 3′-hydroxylation of cotinine in human liver microsomes.
        J Pharmacol Exp Ther. 1996; 277: 1010-1015
        • Newton D.J
        • Wang R.W
        • Lu A.Y
        Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes.
        Drug Metab Dispos Biol Fate Chem. 1995; 23: 154-158
        • Otani K
        • Mihara K
        • Yasui N
        • Ishida M
        • Kondo T
        • Tokinaga N
        • et al.
        Plasma concentrations of trazodone and m-chlorophenylpiperazine at steady state can be predicted from those after an initial dose of trazodone.
        Prog Neuropsychopharmacol Biol Psychiatry. 1997; 21: 239-244
        • Pearce R.E
        • Rodrigues A.D
        • Goldstein J.A
        • Parkinson A
        Identification of the human P450 enzymes involved in iansoprazole metabolism.
        J Pharmacol Exp Ther. 1996; 277: 805-816
        • Remmel R.P
        • Burchell B
        Validation and use of cloned, expressed human drug-metabolizing enzymes in heterologous cells for analysis of drug metabolism and drug–drug interactions.
        Biochem Pharmacol. 1993; 46: 559-566
        • Ring B.J
        • Catlow J
        • Lindsay T.J
        • Gillespie T
        • Roskos L.K
        • Cerimele B.J
        • 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: 658-666
        • Rosenbaum J.F
        Managing selective serotonin reuptake inhibitor-drug interactions in clinical practice.
        Clin Pharmacokinet. 1995; 29: 53-59
        • Samanin R
        • Mennini T
        • Ferraris A
        • Bendotti C
        • Borsini F
        • Garattini S
        Naunyn Schmiedebergs Arch Pharmacol. 1979; 308: 159-163
        • Shen W.W
        Cytochrome P450 monooxygenase and interactions of psychotropic drugs.
        Int J Psychiatry Med. 1995; 25: 277-290
        • Taylor D
        • Lader M
        Cytochromes and psychotropic drug interactions.
        Br J Psychiatry. 1996; 168: 529-532
        • Taylor D.P
        • Carter R.B
        • Eison A.S
        • Mullins U.L
        • Smith H.L
        • Torrente J.R
        • et al.
        Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug.
        J Clin Psychiatry. 1995; 56: 3-11
        • Tu Z.G
        • Zhao L.L
        Inhibitory effects of quinidine and quinine on liver microsome oxidation enzymes in man and rat.
        Acta Pharmacol Sinica. 1996; 17: 541-544
        • Tucker G.T
        The rational selection of drug interaction studies.
        Int J Clin Pharmacol Ther Toxicol. 1992; 30: 550-553
        • von Moltke L.L
        • Greenblatt D.J
        • Cotreau-Bibbo M.M
        • Duan S.X
        • Harmatz J.S
        • Shader R.I
        Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole.
        J Pharmacol Exp Ther. 1994; 268: 1278-1283
        • von Moltke L.L
        • Greenblatt D.J
        • Duan S.X
        • Harmatz J.S
        • Wright C.E
        • Shader R.I
        Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants.
        J Clin Psychopharmacol. 1996; 16: 104-112
        • Walsh A.E.S
        • Smith K.A
        • Oldman A.D
        • Williams C
        • Goodall E.M
        • Cowen P.J
        m-Chlorophenylpiperazine decreases food intake in a test meal.
        Psychopharmacology. 1994; 116: 120-122
        • Wrighton S.A
        • Vandenbranden M
        • Stevens J.C
        • Shipley L.A
        • Ring B.J
        In vitro methods for assessing human hepatic drug metabolism.
        Drug Metab Rev. 1993; 25: 453-484