The Complexity of Active Metabolites in Therapeutic Drug Monitoring of Psychotropic Drugs

In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.

References

• 1 Alfaro C L, Lam Y W, Simpson J, Ereshefsky L. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations.  J Clin Pharmacol. 2000;  40 58-66
• 2 Aravagiri M, Marder S R. Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats.  Psychopharmacology (Berl). 2002;  159 424-431
• 3 Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M. et al . The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.  Pharmacopsychiatry. 2004;  37 243-265
• 4 Baumann P, Jonzier-Perey M, Koeb L, Kupfer A, Tinguely D, Schopf J. Amitriptyline pharmacokinetics and clinical response: II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin.  Int Clin Psychopharmacol. 1986;  1 102-112
• 5 Baumann P, Meyer J W, Amey M, Baettig D, Bryois C, Jonzier-Perey M. et al . Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.  Ther Drug Monit. 1992;  14 1-8
• 6 Abdel-Rahman S M, Gotschall R R, Kauffman R E, Leeder J S, Kearns G L. Investigation of terbinafine as a CYP2D6 inhibitor in vivo.  Clin Pharmacol Ther. 1999;  65 465-472
• 7 Benfield D P, Harries C M, Luscombe D K. Some pharmacological aspects of desmethylclomipramine.  Postgrad Med J. 1980;  56 (Suppl 1) 13-18
• 8 Brosen K, Klysner R, Gram L F, Otton S V, Bech P, Bertilsson L. Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism.  Eur J Clin Pharmacol. 1986;  30 679-684
• 9 Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J. et al . The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.  Eur Neuropsychopharmacol. 2002;  12 461-475
• 10 de L J, Susce M T, Pan R M, Fairchild M, Koch W H, Wedlund P J. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation.  J Clin Psychiatry. 2005;  66 15-27
• 11 Doran A, Obach R S, Smith B J, Hosea N A, Becker S, Callegari E. et al . The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model.  Drug Metab Dispos. 2005;  33 (1) 165-174
• 12 Eap C B, Bondolfi G, Zullino D, Savary-Cosendai L, Powell-Golay K, Kosel M, Baumann P. Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers.  J Clin Psychopharmacol. 2001;  21 330-334
• 13 Fuller R W, Snoddy H D, Krushinski J H, Robertson D W. Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo.  Neuropharmacology. 1992;  31 997-1000
• 14 Grauer M T, Uhr M. P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline.  J Psychopharmacol. 2004;  18 66-74
• 15 Guzey C, Norstrom A, Spigset O. Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion.  Ther Drug Monit. 2002;  24 436-437
• 16 Huang M L, Van P A, Woestenborghs R, De C R, Heykants J, Jansen A A. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
• 17 Jeppesen U, Gram L F, Vistisen K, Loft S, Poulsen H E, Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine.  Eur J Clin Pharmacol. 1996;  51 73-78
• 18 Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers.  Pharmacogenetics. 2002;  12 571-580
• 19 Kohnke M D, Griese E U, Stosser D, Gaertner I, Barth G. Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone.  Pharmacopsychiatry. 2002;  35 116-118
• 20 Kosel M, Gnerre C, Voirol P, Amey M, Rochat B, Bouras C. et al . In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations.  Mol Psychiatry. 2002;  7 181-188
• 21 Koyama E, Tanaka T, Chiba K, Kawakatsu S, Morinobu S, Totsuka S, Ishizaki T. Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients.  J Clin Psychopharmacol. 1996;  16 286-293
• 22 Kuoppamaki M, Syvalahti E, Hietala J. Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists.  Eur J Pharmacol. 1993;  245 179-182
• 23 Liu Z Q, Cheng Z N, Huang S L, Chen X P, Ou-Yang D S, Jiang C H, Zhou H H. Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects.  Br J Clin Pharmacol. 2001;  52 96-99
• 24 LLerena A, Berecz R, Dorado P, de la R A. QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations.  J Psychopharmacol. 2004;  18 189-193
• 25 LLerena A, Dorado P, Berecz R, Gonzalez A P, Penas-LLedo E M. Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions.  Eur J Clin Pharmacol. 2004;  59 869-873
• 26 Mannens G, Meuldermans W, Snoeck E, Heykants J. Plasma protein binding of risperidone and its distribution in blood.  Psychopharmacology (Berl). 1994;  114 566-572
• 27 Morinobu S, Tanaka T, Kawakatsu S, Totsuka S, Koyama E, Chiba K. et al . Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy.  Psychiatry Clin Neurosci. 1997;  51 253-257
• 28 Muth E A, Haskins J T, Moyer J A, Husbands G E, Nielsen S T, Sigg E B. Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative.  Biochem Pharmacol. 1986;  35 4493-4497
• 29 Nesvåg R, Hendset M, Refsum H, Tanum L. Serum concentrations of risperidone and 9-OH risperidone following intramuscular injection of long-acting risperidone compared with oral risperidone medication. In press. 
• 30 Noguchi T, Shimoda K, Takahashi S. Clinical significance of plasma levels of clomipramine, its hydroxylated and desmethylated metabolites: prediction of clinical outcome in mood disorders using discriminant analysis of therapeutic drug monitoring data.  J Affect Disord. 1993;  29 267-279
• 31 Nunez R, Perel J M. Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine.  Psychopharmacol Bull. 1995;  31 217-221
• 32 Pike E, Skuterud B. Plasma binding variations of amitriptyline and nortriptyline.  Clin Pharmacol Ther. 1982;  32 228-234
• 33 Pinder R M, Brogden R N, Speight T M, Avery G S. Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression.  Drugs. 1977;  13 161-218
• 34 Pollock B G, Perel J M. Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine.  Psychopharmacology (Berl). 1992;  109 57-62
• 35 Product i nformation. Anafranil (clomipramine). Oslo, Norway; Novartis 28 - 5-2004
• 36 Product i nformation. Efexor (venlafaxine). Solna, Sweden; Wyeth Lederle 4 - 7-2005
• 37 Product i nformation. Fontex (fluoxetine). Oslo, Norway; Eli Lilly 19 - 1-2005
• 38 Ravindranath V. Metabolism of xenobiotics in the central nervous system: implications and challenges.  Biochem Pharmacol. 1998;  56 547 - 551
• 39 Rudorfer M V, Potter W Z. The role of metabolites of antidepressants in the treatment of depression.  Cns Drugs. 1997;  7 273-312
• 40 Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding.  Cell Mol Neurobiol. 1999;  19 467-489
• 41 Sasongko L, Link J M, Muzi M, Mankoff D A, Yang X, Collier A C. et al . Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography.  Clin Pharmacol Ther. 2005;  77 503-514
• 42 Schinkel A H, Wagenaar E, Mol C A, van D L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.  J Clin Invest. 1996;  97 2517-2524
• 43 Scordo M G, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology (Berl). 1999;  147 300-305
• 44 Shimoda K, Someya T, Yokono A, Morita S, Hirokane G, Takahashi S, Okawa M. The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients.  J Clin Psychopharmacol. 2002;  22 371-378
• 45 Sim S C, Risinger C, Dahl M L, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.  Clin Pharmacol Ther. 2006;  79 103-113
• 46 Sur C, Mallorga P J, Wittmann M, Jacobson M A, Pascarella D, Williams J B. et al . N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity.  Proc Natl Acad Sci U S A. 2003;  100 13 674-13 679
• 47 Szymura-Oleksiak J, Wyska E, Wasieczko A. Pharmacokinetic interaction between imipramine and carbamazepine in patients with major depression.  Psychopharmacology (Berl). 2001;  154 38-42
• 48 Uhr M, Grauer M T, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.  Biol Psychiatry. 2003;  54 840-846
• 49 Uhr M, Steckler T, Yassouridis A, Holsboer F. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption.  Neuropsychopharmacology. 2000;  22 380-387
• 50 van Beijsterveldt L E, Geerts R J, Leysen J E, Megens A A, Van den Eynde H M, Meuldermans W E, Heykants J J. Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.  Psychopharmacology (Berl). 1994;  114 53-62
• 51 Veefkind A H, Haffmans P M, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype.  Ther Drug Monit. 2000;  22 202-208
• 52 Virtanen R, Iisalo E, Irjala K. Protein binding of doxepin and desmethyldoxepin.  Acta Pharmacol Toxicol (Copenh). 1982;  51 159-164
• 53 Wang J S, Ruan Y, Taylor R M, Donovan J L, Markowitz J S, DeVane C L. The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein.  Int J Neuropsychopharmacol. 2004;  7 415-419
• 54 Weiner D M, Meltzer H Y, Veinbergs I, Donohue E M, Spalding T A, Smith T T. et al . The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.  Psychopharmacology (Berl). 2004;  177 207-216
• 55 Wong D T, Bymaster F P, Reid L R. Inhibition of serotonin uptake by optical isomers of fluoxetine.  Drug Dev Res. 1985;  6 397-403
• 56 Wong D T, Bymaster F P, Reid L R, Mayle D A, Krushinski J H, Robertson D W. Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain.  Neuropsychopharmacology. 1993;  8 337-344
• 57 Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo M G, Tybring G. Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes.  Drug Metab Dispos. 2001;  29 1263-1268
• 58 Yokono A, Morita S, Someya T, Hirokane G, Okawa M, Shimoda K. The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients.  J Clin Psychopharmacol. 2001;  21 549-555
• 59 Zhang Y, Britto M R, Valderhaug K L, Wedlund P J, Smith R A. Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6.  Clin Pharmacol Ther. 1992;  51 647-655