Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 7, 2012, Pages 833-854

  Wong, Yin Cheong ^a   Qian, Shuai ^a   Zuo, Zhong ^a  

^a Prince of Wales Hospital   (Hong Kong)

Author keywords

adverse drug reactions; cytochrome P450; drug administration routes; glucuronosyltransferase; in silico prediction; metabolite toxicity; regioselective biotransformation; structure modification

Indexed keywords

ALPIDEM; AMITRIPTYLINE; AMOXAPINE; ANTICONVULSIVE AGENT; BUPIVACAINE; CARBAMAZEPINE; CHLORPROMAZINE; CLOZAPINE; DEXTROPROPOXYPHENE; DULOXETINE; ENFLURANE; FELBAMATE; FLUNITRAZEPAM; HALOPERIDOL; HALOTHANE; IMIPRAMINE; LOXAPINE; MIDAZOLAM; MORPHINE; NEUROLEPTIC AGENT; NOMIFENSINE; PETHIDINE; PHENOTHIAZINE; RISPERIDONE; SELEGILINE; TACRINE; TOLCAPONE; TRICYCLIC ANTIDEPRESSANT AGENT; UNINDEXED DRUG; XENOBIOTIC AGENT;

ADVERSE DRUG REACTION; AGRANULOCYTOSIS; APLASTIC ANEMIA; AREA UNDER THE CURVE; BLOOD TOXICITY; CARDIOTOXICITY; CENTRAL NERVOUS SYSTEM ASPERGILLOSIS; COMPUTER MODEL; DRUG DELIVERY SYSTEM; DRUG DETOXIFICATION; DRUG TRANSFORMATION; DRUG WITHDRAWAL; EYE TOXICITY; HEMOLYTIC ANEMIA; HUMAN; LIVER TOXICITY; MAXIMUM PLASMA CONCENTRATION; MEDICAL RESEARCH; NEPHROTOXICITY; NEUROTOXICITY; NONHUMAN; PREDICTION; REVIEW; SCHIZOPHRENIA; SEIZURE; SKIN TOXICITY; TERATOGENICITY;

ANIMALS; ANTICONVULSANTS; ANTIPSYCHOTIC AGENTS; BIOTRANSFORMATION; CENTRAL NERVOUS SYSTEM AGENTS; DRUG TOXICITY; HUMANS; METABOLIC DETOXICATION, DRUG; XENOBIOTICS;

EID: 84862573430     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.688027     Document Type: Review

References (205)

1. Brown CM, Reisfeld B, Mayeno AN. Cytochromes P450: a structure-based summary of biotransformations using representative substrates. Drug Metab Rev 2008;40:1-100 Sites of metabolism and the isoforms involved in the metabolisms of 113 xenobiotics are presented in a tabular format.
2. Testa B, Pedretti A, Vistoli G. Reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug Discov Today 2012;published online 2012/02/07; doi: 10.1016/j.drudis.2012.01.017
3. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009;48:761-804 A comprehensive review on how polymorphisms affect clinical outcomes of CNS drugs.
4. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet 2009;48:689-723
5. Wang B, Yang LP, Zhang XZ, et al. New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab Rev 2009;41:573-643 Detailed discussions on how the protein structure of CYP2D6 is related to ligand binding.
6. Unwalla RJ, Cross JB, Salaniwal S, et al. Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism. J Comput Aided Mol Des 2010;24:237-56
7. Wu BJ, Basu S, Meng SN, et al. Regioselective sulfation and glucuronidation of phenolics: insights into the structural basis. Curr Drug Metab 2011;12:900-16 An up-to-date review summarizing the regioselectivities of UGTs and SULTs with discussions on the protein structure.
8. Jager AK, Saaby L. Flavonoids and the CNS. Molecules 2011;16:1471-85
9. Wong YC, Zhang L, Lin G, et al. Structure - activity relationships of the glucuronidation of flavonoids by human glucuronosyltransferases. Expert Opin Drug Metab Toxicol 2009;5:1399-419 A comprehensive review summarizing the various aspects of UGTs regioselectivity towards flavonoids based on the chemical structure of flavonoids.
10. Singh R, Wu BJ, Tang L, et al. Uridine diphosphate glucuronosyltransferase isoform-dependent regiospecificity of glucuronidation of flavonoids. J Agric Food Chem 2011;59:7452-64
11. Wong YC, Zhang L, Lin G, et al. Intestinal first-pass glucuronidation activities of selected dihydroxyflavones. Int J Pharm 2009;366:14-20
12. Kaivosaari S, Finel M, Koskinen M. N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases. Xenobiotica 2011;41:652-69
13. Torres RA, Korzekwa KR, McMasters DR, et al. Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase. J Med Chem 2007;50:4642-7 (Pubitemid 47463238)
14. Lomri N, Yang ZC, Cashman JR. Regio-selective and stereoselective oxygenations by adult human liver flavin-containing monooxygenase. 3. Comparison with form-1 and form-2. Chem Res Toxicol 1993;6:800-7 (Pubitemid 23351202)
15. Schuster D, Laggner C, Langer T. Why drugs fail - a study on side effects in new chemical entities. Curr Pharm Des 2005;11:3545-59 (Pubitemid 41300759)
16. Zhou SF, Chan E, Duan W, et al. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 2005;37:41-213 Detailed characterization of the bioactivation pathways of a great number of drugs. (Pubitemid 40259715)
17. Kalgutkar AS, Soglia JR. Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 2005;1:91-142 Detailed discussion of the bioactivation pathways of drugs and strategies to abrogate reactive metabolite formation.
18. Benedetti MS, Whomsley R, Baltes E. Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin Drug Metab Toxicol 2006;2:895-921 (Pubitemid 44911539)
19. Oesch-Bartlomowicz B, Oesch F. Mechanisms of toxification and detoxification that challenge drug candidates and drugs. In: Testa B, van de Waterbeemd H, editors. Comprehensive Medicinal Chemistry II. Volume 5 ADME-Tox Approaches Elsevier; UK: 2007. p. 193-214
20. Chakrabarti A, Bagnall A, Chue P, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev 2007;CD001943
21. Huie K, Reed A, Takahashi L, et al. Characterization of loxapine human metabolism. Drug Metab Rev 2008;40:210-11
22. Luo JP, Vashishtha SC, Hawes EM, et al. In vitro identification of the human cytochrome p450 enzymes involved in the oxidative metabolism of loxapine. Biopharm Drug Dispos 2011;32:398-407
23. Granvil CP, Chen J, Padval MV, et al. In vitro metabolism of CRx-119, a novel syncretic drug candidate, in human liver microsomes and recombinant P450 enzymes. Drug Metab Rev 2006;38:94
24. Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry 1999;60:20-30 (Pubitemid 29237172)
25. Cohen BM, Harris PQ, Altesman RI, et al. Amoxapine: neuroleptic as well as antidepressant? Am J Psychiatry 1982;139:1165-7 (Pubitemid 12037789)
26. Chaudhry IB, Husain N, Khan S, et al. Amoxapine as an antipsychotic: comparative study versus haloperidol. J Clin Psychopharmacol 2007;27:575-81 (Pubitemid 351339443)
27. Apiquian R, Fresan A, Ulloa RE, et al. Amoxapine as an atypical antipsychotic: a comparative study vs risperidone. Neuropsychopharmacology 2005;30:2236-44 (Pubitemid 41643975)
28. Coupet J, Rauh CE. 3H-Spiroperidol binding to dopamine receptors in rat striatal membranes: influence of loxapine and its hydroxylated metabolites. Eur J Pharmacol 1979;55:215-18 (Pubitemid 9215642)
29. Dayalu P, Chou KL. Antipsychotic-induced extrapyramidal symptoms and their management. Expert Opin Pharmacother 2008;9:1451-62 (Pubitemid 352005909)
30. Rudorfer MV, Potter WZ. Antidepressants a comparative review of the clinical-pharmacology and therapeutic use of the newer versus the older drugs. Drugs 1989;37:713-38 (Pubitemid 19138618)
31. Cooper TB, Bost R, Sunshine I. Postmortem blood and tissue levels of loxapine and its metabolites. J Anal Toxicol 1981;5:99-100 (Pubitemid 11100974)
32. Wong YC, Wo SK, Zuo Z. Investigation of the disposition of loxapine, amoxapine and their hydroxylated metabolites in different brain regions, CSF and plasma of rat by LC-MS/MS. J Pharm Biomed Anal 2012;58:83-93
33. Cheung SW, Tang SW, Remington G. Simultaneous quantitation of loxapine, amoxapine and their 7-hydroxy and 8-hydroxy metabolites in plasma by high-performance liquid-chromatography. J Chromatogr 1991;564:213-21
34. Hue B, Palomba B, Giacardy-Paty M, et al. Concurrent high-performance liquid chromatographic measurement of loxapine and amoxapine and of their hydroxylated metabolites in plasma. Ther Drug Monit 1998;20:335-9 (Pubitemid 28248856)
35. Kumlien E, Lundberg PO. Seizure risk associated with neuroactive drugs: data from the WHO adverse drug reactions database. Seizure 2010;19:69-73
36. Peterson CD. Seizures induced by acute loxapine overdose. Am J Psychiatry 1981;138:1089-91 (Pubitemid 11012812)
37. Coccia PF, Westerfeld WW. The metabolism of chlorpromazine by liver microsomal enzyme systems. J Pharmacol Exp Ther 1967;157:446-58
38. Mackay AVP, Healey AF, Baker J. The relationship of plasma chlorpromazine to its 7-hydroxy and sulphoxide metabolites in a large population of chronic schizophrenics. Br J Clin Pharmacol 1974;1:425-30
39. Phillipson OT, Mckeown JM, Baker J, et al. Correlation between plasma chlorpromazine and its metabolites and clinical ratings in patients with acute relapse of schizophrenic and paranoid psychosis. Br J Psychiatry 1977;131:172-84 (Pubitemid 8155827)
40. Alfredsson G, Lindberg M, Sedvall G. The presence of 7- hydroxychlorpromazine in CSF of chlorpromazine-treated patients. Psychopharmacology 1982;77:376-8 (Pubitemid 12061705)
41. Wen B, Zhou MY. Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s. Chem Biol Interact 2009;181:220-6
42. Guo JJ, Wigle PR, Lammers K, et al. Comparison of potentially hepatotoxic drugs among major US drug compendia. Res Social Adm Pharm 2005;1:460-79 (Pubitemid 44061732)
43. Tijoe SA, Manian AA, O'Neill JJ. Effects of hydroxylated phenothiazine metabolites on rat brain mitochondria. Adv Biochem Psychopharmacol 1974;9:603-16
44. Heikkila RE, Cohen G, Manian AA. Reactivity of various phenothiazine derivatives with oxygen and oxygen radicals. Biochem Pharmacol 1975;24:363-8
45. Buckley JP, Steenberg ML, Barry H III, et al. Pharmacology of mono- and disubstituted chlorpromazine metabolites. J Pharm Sci 1973;62:715-22
46. Perry TL, Culling CF, Berry K, et al. 7- Hydroxychlorpromazine: potential toxic drug metabolite in psychiatric patients. Science 1964;146:81-3
47. Adams HR, Manian AA, Steenberg ML, et al. Effects of promazine and chlorpromazine metabolites on the cornea. Adv Biochem Psychopharmacol 1974;9:281-93
48. Watson RG, Olomu A, Clements D, et al. A proposed mechanism for chlorpromazine jaundice - defective hepatic sulphoxidation combined with rapid hydroxylation. J Hepatol 1988;7:72-8
49. Elias E, Boyer JL. Chlorpromazine and its metabolites alter polymerization and gelation of actin. Science 1979;206:1404-6 (Pubitemid 10181464)
50. Wojcikowski J, Boksa J, Daniel WA. Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver - A comparison with other phenothiazines. Biochem Pharmacol 2010;80:1252-9
51. Lin G, Hawes EM, McKay G, et al. Metabolism of piperidine-type phenothiazine antipsychotic agents. IV. Thioridazine in dog, man and rat. Xenobiotica 1993;23:1059-74 (Pubitemid 23324229)
52. Thanacoody RH, Daly AK, Reilly JG, et al. Factors affecting drug concentrations and QT interval during thioridazine therapy. Clin Pharmacol Ther 2007;82:555-65 (Pubitemid 47622522)
53. Heath A, Svensson C, Martensson E. Thioridazine toxicity - an experimental cardiovascular study of thioridazine and its major metabolites in overdose. Vet Hum Toxicol 1985;27:100-5
54. Hale PW Jr, Poklis A. Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine 5-sulfoxide in the isolated perfused rat heart. Toxicol Appl Pharmacol 1986;86:44-55 (Pubitemid 17170473)
55. Midha KK, Hubbard JW, Marder SR, et al. Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia. J Psychiatry Neurosci 1994;19:254-64 (Pubitemid 24230501)
56. Post RM, Ketter TA, Uhde T, et al. Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness: principles and practice. CNS Drugs 2007;21:47-71 (Pubitemid 46072350)
57. Lertratanangkoon K, Horning MG. Metabolism of carbamazepine. Drug Metab Dispos 1982;10:1-10 (Pubitemid 12177378)
58. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994;47:1969-79
59. Yuki H, Honma T, Hata M, et al. Prediction of sites of metabolism in a substrate molecule, instanced by carbamazepine oxidation by CYP3A4. Bioorg Med Chem 2012;20:775-83
60. Nakamura H, Torimoto N, Ishii I, et al. CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. Drug Metab Dispos 2003;31:432-8 (Pubitemid 36378520)
61. Bu HZ, Kang P, Deese AJ, et al. Human in vitro glutathionyl and protein adducts of carbamazepine-10,11-epoxide, a stable and pharmacologically active metabolite of carbamazepine. Drug Metab Dispos 2005;33:1920-4 (Pubitemid 41697278)
62. Bennett GD, Amore BM, Finnell RH, et al. Teratogenicity of carbamazepine-10, 11-epoxide and oxcarbazepine in the SWV mouse. J Pharmacol Exp Ther 1996;279:1237-42 (Pubitemid 27166770)
63. Wu Y, Sanderson JP, Farrell J, et al. Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol 2006;118:233-41 (Pubitemid 43964854)
64. Kerr BM, Rettie AE, Eddy AC, et al. Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation. Clin Pharmacol Ther 1989;46:82-93 (Pubitemid 19195778)
65. Kitteringham NR, Davis C, Howard N, et al. Interindividual and interspecies variation in hepatic microsomal epoxide hydrolase activity: studies with cis-stilbene oxide, carbamazepine 10, 11-epoxide and naphthalene. J Pharmacol Exp Ther 1996;278:1018-27
66. Staud F, Ceckova M, Micuda S, et al. Expression and function of p-glycoprotein in normal tissues: effect on pharmacokinetics. Methods Mol Biol 2010;596:199-222
67. Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 2005;76:22-76 (Pubitemid 41033402)
68. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol 2008;18:157-69
69. Zhang C, Kwan P, Zuo Z, et al. The transport of antiepileptic drugs by P-glycoprotein. Adv Drug Deliv Rev 2011;published online 2011/12/27, doi: 10.1016/j.addr.2011.12.003
70. Takayasu T, Ishida Y, Kimura A, et al. Distribution of carbamazepine and its metabolites carbamazepine-10,11-epoxide and iminostilbene in body fluids and organ tissues in five autopsy cases. Forensic Toxicol 2010;28:124-8
71. Pitterle ME, Collins DM. Carbamazepine-10-11-epoxide evaluation associated with coadministration of loxapine or amoxapine [abstract]. Epilepsia 1988;29:654
72. Palmeira A, Rodrigues F, Sousa E, et al. New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem Biol Drug Des 2011;78:57-72
73. Besag FMC, Berry D. Interactions between antiepileptic and antipsychotic drugs. Drug Safety 2006;29:95-118 (Pubitemid 43213885)
74. Potter JM, Donnelly A. Carbamazepine- 10,11-epoxide in therapeutic drug monitoring. Ther Drug Monit 1998;20:652-7 (Pubitemid 28544295)
75. Ghosh C, Marchi N, Hossain M, et al. A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain. Neurobiol Dis 2012;published online 2012/03/20; doi: 10.1016/j.nbd.2012.03.010
76. Gorski JC, Hall SD, Jones DR, et al. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 1994;47:1643-53 (Pubitemid 24167278)
77. Roberts AG, Yang J, Halpert JR, et al. The structural basis for homotropic and heterotropic cooperativity of midazolam metabolism by human cytochrome P450 3A4. Biochemistry 2011;50:10804-18
78. Yang J, Atkins WM, Isoherranen N, et al. Evidence of CYP3A allosterism in vivo: analysis of interaction between fluconazole and midazolam. Clin Pharmacol Ther 2012;91:442-9
79. Seo KA, Bae SK, Choi YK, et al. Metabolism of 1'- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. Drug Metab Dispos 2010;38:2007-13
80. Hyland R, Osborne T, Payne A, et al. In vitro and in vivo glucuronidation of midazolam in humans. Br J Clin Pharmacol 2009;67:445-54
81. Mandema JW, Tuk B, van Steveninck AL, et al. Pharmacokinetic- pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther 1992;51:715-28
82. Clausen TG, Wolff J, Hansen PB, et al. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol 1988;25:457-63
83. Boulieu R, Lehmann B, Salord F, et al. Pharmacokinetics of midazolam and its main metabolite 1-hydroxymidazolam in intensive care patients. Eur J Drug Metab Pharmacokinet 1998;23:255-8 (Pubitemid 28401116)
84. Bauer TM, Ritz R, Haberthur C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 1995;346:145-7
85. Swart EL, de Jongh J, Zuideveld KP, et al. Population pharmacokinetics of lorazepam and midazolam and their metabolites in intensive care patients on continuous venovenous hemofiltration. Am J Kidney Dis 2005;45:360-71 (Pubitemid 40431063)
86. Harder JL, Heung M, Vilay AM, et al. Carbamazepine and the active epoxide metabolite are effectively cleared by hemodialysis followed by continuous venovenous hemodialysis in an acute overdose. Hemodial Int 2011;15:412-15
87. Caccia S, Garattini S. Formation of active metabolites of psychotropic drugs. An updated review of their significance. Clin Pharmacokinet 1990;18:434-59 (Pubitemid 20183887)
88. Steimer W, Zopf K, von Amelunxen S, et al. Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem 2005;51:376-85 (Pubitemid 40175808)
89. Uhr M, Grauer MT, Yassouridis A, et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res 2007;41:179-88 (Pubitemid 44708204)
90. Roberts RL, Joyce PR, Mulder RT, et al. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J 2002;2:191-6 (Pubitemid 34982226)
91. Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett 2010;197:157-62
92. Fattore L, Fratta W. Beyond THC: the new generation of cannabinoid designer drugs. Front Behav Neurosci 2011;5:60
93. Dresen S, Ferreiros N, Putz M, et al. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J Mass Spectrom 2010;45:1186-94
94. Moran CL, Le VH, Chimalakonda KC, et al. Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem 2011;83:4228-36
95. Brents LK, Reichard EE, Zimmerman SM, et al. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 2011;6:e21917
96. Brents LK, Gallus-Zawada A, Radominska-Pandya A, et al. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol 2012;83:952-61
97. Ginsburg BC, Schulze DR, Hruba L, et al. JWH-018 and JWH-073: delta(9)- tetrahydrocannabinol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 2012;340:37-45
98. Chimalakonda KC, Bratton SM, Le VH, et al. Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP- glucuronosyltransferases. Drug Metab Dispos 2011;39:1967-76
99. Mishra NK. Computational modeling of P450s for toxicity prediction. Expert Opin Drug Metab 2011;7:1211-31
100. Kirchmair J, Williamson MJ, Tyzack JD, et al. Computational prediction of metabolism: sites, products, SAR, P450 enzyme dynamics, and mechanisms. J Chem Inf Model 2012;published online 2012/02/22, doi: 10.1021/ci200542m
101. Tarcsay A, Keseru GM. In silico site of metabolism prediction of cytochrome P450-mediated biotransformations. Expert Opin Drug Metab Toxicol 2011;7:299-312
102. de Groot MJ, Ackland MJ, Horne VA, et al. Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6. J Med Chem 1999;42:1515-24 (Pubitemid 29226723)
103. T'Jollyn H, Boussery K, Mortishire-Smith RJ, et al. Evaluation of three state-of-the-art metabolite prediction software packages (Meteor, MetaSite, and StarDrop) through independent and synergistic use. Drug Metab Dispos 2011;39:2066-75
104. Pujol A, Mosca R, Farres J, et al. Unveiling the role of network and systems biology in drug discovery. Trends Pharmacol Sci 2010;31:115-23
105. van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2003;2:192-204
106. Norinder U. In silico modelling of ADMET-a minireview of work from 2000 to 2004. SAR QSAR Environ Res 2005;16:1-11 (Pubitemid 40623240)
107. Madden JC, Cronin MT. Structure-based methods for the prediction of drug metabolism. Expert Opin Drug Metab Toxicol 2006;2:545-57 (Pubitemid 46118325)
108. Czodrowski P, Kriegl JM, Scheuerer S, et al. Computational approaches to predict drug metabolism. Expert Opin Drug Metab Toxicol 2009;5:15-27
109. Ekins S, Andreyev S, Ryabov A, et al. A combined approach to drug metabolism and toxicity assessment. Drug Metab Dispos 2006;34:495-503 (Pubitemid 43290909)
110. Sun H, Scott DO. Structure-based drug metabolism predictions for drug design. Chem Biol Drug Des 2010;75:3-17
111. Krieger E, Koraimann G, Vriend G. Increasing the precision of comparative models with YASARA NOVA - A self-parameterizing force field. Proteins 2002;47:393-402 (Pubitemid 34438688)
112. Braga RC, Alves VM, Fraga CA, et al. Combination of docking, molecular dynamics and quantum mechanical calculations for metabolism prediction of 3,4-methylenedioxybenzoyl-2- thienylhydrazone. J Mol Model 2011;published online 2011/09/09, doi: 10.1007/s00894-011-1219-9
113. Kapetanovic IM, Torchin CD, Thompson CD, et al. Potentially reactive cyclic carbamate metabolite of the antiepileptic drug felbamate produced by human liver tissue in vitro. Drug Metab Dispos 1998;26:1089-95 (Pubitemid 28516584)
114. Parker RJ, Hartman NR, Roecklein BA, et al. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions. Chem Res Toxicol 2005;18:1842-8 (Pubitemid 43023042)
115. Kapetanovic IM, Torchin CD, Strong JM, et al. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem Biol Interact 2002;142:119-34 (Pubitemid 35238045)
116. Thompson CD, Gulden PH, Macdonald TL. Identification of modified atropaldehyde mercapturic acids in rat and human urine after felbamate administration. Chem Res Toxicol 1997;10:457-62 (Pubitemid 27176309)
117. Thompson CD, Barthen MT, Hopper DW, et al. Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids. Epilepsia 1999;40:769-76 (Pubitemid 29260718)
118. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 2008;7:255-70 Important reference giving an excellent overview of structure modification via prodrugs approach for drug design. (Pubitemid 351324639)
119. Stella VJ. Prodrugs: some thoughts and current issues. J Pharm Sci 2010;99:4755-65
120. Gonzalez JP, Brogden RN. Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988;35:192-213
121. Johnson FK, Stark JG, Bieberdorf FA, et al. Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: a single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers. Clin Ther 2010;32:1149-64
122. Hussain MA, Koval CA, Myers MJ, et al. Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach. J Pharm Sci 1987;76:356-8 (Pubitemid 17119895)
123. Wong YC, Zuo Z. Intranasal delivery-Modification of drug metabolism and brain disposition. Pharm Res 2010;27:1208-23
124. Christrup LL. Morphine metabolites. Acta Anaesthesiol Scand 1997;41:116-22 (Pubitemid 27072914)
125. Osborne RJ, Joel SP, Slevin ML. Morphine intoxication in renal failure - the role of morphine-6-glucuronide. Br Med J 1986;292:1548-9 (Pubitemid 16080832)
126. Vaughan CW, Connor M. In search of a role for the morphine metabolite morphine-3-glucuronide. Anesth Analg 2003;97:311-12 (Pubitemid 36899723)
127. Illum L, Watts P, Fisher AN, et al. Intranasal delivery of morphine. J Pharmacol Exp Ther 2002;301:391-400 (Pubitemid 34250318)
128. Batheja P, Thakur R, Michniak B. Basic biopharmaceutics of buccal and sublingual absorption. In: Touitou E, Barry BW, editors. Enhancement in Drug Delivery. CRC Press; Boca Raton, FL; 2006. p. 175-202
129. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharm Sci 1998;1:15-30
130. Goswami T, Jasti B, Li XL. Sublingual drug delivery. Crit Rev Ther Drug Carrier Syst 2008;25:449-84
131. Blonk MI, Koder BG, van den Bemt PMLA, et al. Use of oral ketamine in chronic pain management: a review. Eur J Pain 2010;14:466-72
132. Yanagihara Y, Ohtani M, Kariya S, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 2003;24:37-43 (Pubitemid 36124167)
133. Hidestrand M, Oscarson M, Salonen JS, et al. CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes. Drug Metab Dispos 2001;29:1480-4 (Pubitemid 33000696)
134. Clarke A, Johnson ES, Mallard N, et al. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm 2003;110:1257-71 (Pubitemid 37500747)
135. Shin HS. Metabolism of selegiline in humans. Identification, excretion, and stereochemistry of urine metabolites. Drug Metab Dispos 1997;25:657-62
136. Malaty IA, Fernandez HH. Role of rasagiline in treating Parkinson's disease: effect on disease progression. Ther Clin Risk Manag 2009;5:413-19
137. Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm 2003;110:1241-55 (Pubitemid 37500746)
138. Putcha L, Cintron NM, Tsui J, et al. Pharmacokinetics and oral bioavailability of scopolamine in normal subjects. Pharm Res 1989;6:481-5 (Pubitemid 19182184)
139. Azzaro AJ, Ziemniak J, Kemper E, et al. Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/ 24 h): a comparison with oral selegiline capsules. J Clin Pharmacol 2007;47:1256-67 (Pubitemid 47459663)
140. Meyer RP, Gehlhaus M, Knoth R, et al. Expression and function of cytochrome P450 in brain drug metabolism. Curr Drug Metab 2007;8:297-306 (Pubitemid 46780059)
141. Dutheil F, Beaune P, Loriot MA. Xenobiotic metabolizing enzymes in the central nervous system: contribution of cytochrome P450 enzymes in normal and pathological human brain. Biochimie 2008;90:426-36
142. Heydel JM, Holsztynska EJ, Legendre A, et al. UDP- glucuronosyltransferases (UGTs) in neuro-olfactory tissues: expression, regulation, and function. Drug Metab Rev 2010;42:74-97
143. Wojcikowski J, Daniel WA. The role of the nervous system in the regulation of liver cytochrome P450. Curr Drug Metab 2011;12:124-38
144. Ascalone V, Catalani P, Dalbo L, et al. Determination of alpidem and its metabolites in human plasma by high performance liquid chromatography and fluorometric detection. J Chromatogr 1987;414:101-8 (Pubitemid 17025771)
145. Kalgutkar AS. Reliability of reactive metabolite and covalent binding assessments in prediction of idiosyncratic drug toxicity. In: Xu JJ, Urban L, editors. Predictive Toxicology in Drug Safety. Cambridge University Press, UK; 2010. p. 102-23
146. Gantenbein M, Attolini L, Bruguerolle B, et al. Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos 2000;28:383-5 (Pubitemid 30185674)
147. Kastrissios H, Hung MF, Triggs EJ. High performance liquid chromatographic method for the quantitation of bupivacaine, 2,6-pipecoloxylidide and 4′-hydroxybupivacaine in plasma and urine. J Chromatogr 1992;577:103-7
148. Bruguerolle B, Attolini L, Gantenbein M. Acute toxicity of bupivacaine metabolites in mice. Clin Exp Pharmacol Physiol 1994;21:997-9
149. Miao XS, Metcalfe CD. Determination of carbamazepine and its metabolites in aqueous samples using liquid chromatography-electrospray tandem mass spectrometry. Anal Chem 2003;75:3731-8 (Pubitemid 36962105)
150. Pirmohamed M, Leeder SJ. Anticonvulsant agents. In: Kaplowitz N, DeLeve LD, editors. Drug-Induced Liver Disease. Informa Healthcare; New York, USA; 2007. p. 485-505
151. Schaber G, Stevens I, Gaertner HJ, et al. Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance. Br J Clin Pharmacol 1998;46:453-9 (Pubitemid 28484732)
152. Wen B, Ma L, Nelson SD, et al. High-throughput screening and characterization of reactive metabolites using polarity switching of hybrid triple quadrupole linear ion trap mass spectrometry. Anal Chem 2008;80:1788-99 (Pubitemid 351429586)
153. Liu ZC, Uetrecht JP. Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells. J Pharmacol Exp Ther 1995;275:1476-83 (Pubitemid 26130647)
154. Gardner I, Zahid N, MacCrimmon D, et al. A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Mol Pharmacol 1998;53:991-8 (Pubitemid 28280440)
155. Lu Y, Meng Q, Zhang G, et al. Clozapine-induced hepatotoxicity in rat hepatocytes by gel entrapment and monolayer culture. Toxicol In Vitro 2008;22:1754-60
156. Macfarlane B, Davies S, Mannan K, et al. Fatal acute fulminant liver failure due to clozapine: a case report and review of clozapine-induced hepatotoxicity. Gastroenterology 1997;112:1707-9 (Pubitemid 27181397)
157. Mosyagin I, Dettling M, Roots I, et al. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol 2004;24:613-17 (Pubitemid 39518656)
158. Lantz RJ, Gillespie TA, Rash TJ, et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003;31:1142-50 (Pubitemid 37048286)
159. Wu G, Vashishtha SC, Erve JC. Characterization of glutathione conjugates of duloxetine by mass spectrometry and evaluation of in silico approaches to rationalize the site of conjugation for thiophene containing drugs. Chem Res Toxicol 2010;23:1393-404
160. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010;32:1174-83
161. Kharasch ED, Thummel KE, Mautz D, et al. Clinical enflurane metabolism by cytochrome P450 2E1. Clin Pharmacol Ther 1994;55:434-40 (Pubitemid 24172968)
162. Njoku D, Laster MJ, Gong DH, et al. Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury. Anesth Analg 1997;84:173-8 (Pubitemid 27020979)
163. Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 1977;46:265-71 (Pubitemid 8071857)
164. Romanyshyn LA, Wichmann JK, Kucharczyk N, et al. Simultaneous determination of felbamate and four metabolites in rat cerebrospinal fluid by high-performance liquid chromatography. J Chromatogr 1993;622:223-8 (Pubitemid 24076163)
165. Dieckhaus CM, Thompson CD, Roller SG, et al. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem Biol Interact 2002;142:99-117 (Pubitemid 35232556)
166. Mizuno K, Katoh M, Okumura H, et al. Metabolic activation of benzodiazepines by CYP3A4. Drug Metab Dispos 2009;37:345-51
167. Feely J, Kavanagh PV, McNamara SM, et al. Simple preparation of the major urinary metabolites of flunitrazepam and nitrazepam. Ir J Med Sci 1999;168:8-9 (Pubitemid 29094945)
168. Seki E, Taniguchi H, Nagano R, et al. Case report: severe hepatic disorder induced by chronic administration of antidepressants drugs. In: 552nd Meeting for the Japanese Society of Internal Medicine Kanto Division; 8 Mar 2008; Tokyo, Japan; 2008. p. 31
169. LinWu SW, Wang AH, Peng FC. Flavin-containing reductase: new perspective on the detoxification of nitrobenzodiazepine. Expert Opin Drug Metab Toxicol 2010;6:967-81
170. Kharasch ED, Hankins D, Mautz D, et al. Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis. Lancet 1996;347:1367-71 (Pubitemid 26147933)
171. Spracklin DK, Thummel KE, Kharasch ED. Human reductive halothane metabolism in vitro is catalyzed by cytochrome P450 2A6 and 3A4. Drug Metab Dispos 1996;24:976-83 (Pubitemid 26314549)
172. Zimmerman HJ. Hepatotoxicity: the Adverse Effects of Drugs and other Chemicals on the Liver. Lippincott Williams & Wilkins; Philadephia, PA: 1999
173. Fraser AD, Susnik E, Isner AF. Analysis of 2-hydroxyimipramine in an imipramine-related fatality. J Forensic Sci 1987;32:543-9 (Pubitemid 17060551)
174. Zeugin TB, Brosen K, Meyer UA. Determination of imipramine and seven of its metabolites in human liver microsomes by a high-performance liquid chromatographic method. Anal Biochem 1990;189:99-102 (Pubitemid 20262984)
175. Takakusa H, Masumoto H, Yukinaga H, et al. Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos 2008;36:1770-9
176. Masubuchi Y, Konishi M, Horie T. Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes. Arch Toxicol 1999;73:147-51 (Pubitemid 29279500)
177. Pollock BG, Perel JM. Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine. Psychopharmacology (Berl) 1992;109:57-62
178. Nelson SD, Mitchell JR, Timbrell JA, et al. Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat. Science 1976;193:901-3
179. Nelson SD, Mitchell JR, Snodgrass WR, et al. Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine. J Pharmacol Exp Ther 1978;206:574-85 (Pubitemid 9037821)
180. Timbrell JA. The role of metabolism in the hepatotoxicity of isoniazid and iproniazid. Drug Metab Rev 1979;10:125-47 (Pubitemid 10185380)
181. Eliott HW, Plotnikoff NP, Way EL. Biotransformation products of meperidine excreted in the urine of man. J Pharmacol Exp Ther 1956;117:414-19
182. Hershey LA. Meperidine and central neurotoxicity. Ann Intern Med 1983;98:548-9 (Pubitemid 13116632)
183. Jiraki K. Lethal effects of normeperidine. Am J Forensic Med Pathol 1992;13:42-3
184. Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther 2002;9:53-68
185. Todaka T, Ishida T, Kita H, et al. Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite. Biol Pharm Bull 2005;28:1275-80 (Pubitemid 41327601)
186. Projean D, Morin PE, Tu TM, et al. Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica 2003;33:841-54 (Pubitemid 37129907)
187. Bosch ME, Sanchez AR, Rojas FS, et al. Morphine and its metabolites: analytical methodologies for its determination. J Pharm Biomed Anal 2007;43:799-815 (Pubitemid 46185826)
188. Kellner HM, Baeder C, Christ O, et al. Kinetics and metabolism of nomifensine in animals. Br J Clin Pharmacol 1977;4(Suppl 2):109S-16S (Pubitemid 8184502)
189. Stepan AF, Walker DP, Bauman J, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 2011;24:1345-410
190. Obach RS, Dalvie DK. Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes. Drug Metab Dispos 2006;34:1310-16 (Pubitemid 44079871)
191. Yu J, Mathisen DE, Burdette D, et al. Identification of multiple glutathione conjugates of 8-amino- 2-methyl-4- phenyl-1,2,3,4- tetrahydroisoquinoline maleate (nomifensine) in liver microsomes and hepatocyte preparations: evidence of the bioactivation of nomifensine. Drug Metab Dispos 2010;38:46-60
192. Salama A, Mueller-Eckhardt C. The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N Engl J Med 1985;313:469-74 (Pubitemid 15015074)
193. Due SL, Sullivan HR, McMahon RE. Propoxyphene: pathways of metabolism in man and laboratory animals. Biomed Mass Spectrom 1976;3:217-25
194. Somogyi AA, Menelaou A, Fullston SV. CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement. Xenobiotica 2004;34:875-87 (Pubitemid 39648167)
195. Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res 1999;44:568-78 (Pubitemid 30012060)
196. Benetton SA, Fang C, Yang YO, et al. P450 phenotyping of the metabolism of selegiline to desmethylselegiline and methamphetamine. Drug Metab Pharmacokinet 2007;22:78-87
197. El-Tawil OS, Abou-Hadeed AH, El-Bab MF, et al. d-Amphetamine-induced cytotoxicity and oxidative stress in isolated rat hepatocytes. Pathophysiology 2011;18:279-85
198. Churchyard A, Mathias CJ, Boonkongchuen P, et al. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson's disease. J Neurol Neurosurg Psychiatry 1997;63:228-34 (Pubitemid 27388974)
199. Qian S, Wo SK, Zuo Z. Pharmacokinetics and brain dispositions of tacrine and its major bioactive monohydroxylated metabolites in rats. J Pharm Biomed Anal 2012;61:57-63
200. Patocka J, Jun D, Kuca K. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. Curr Drug Metab 2008;9:332-5 (Pubitemid 351836422)
201. Park BK, Madden S, Spaldin V, et al. Tacrine transaminitis: potential mechanisms. Alzheimer Dis Assoc Disord 1994;8:S39-49 (Pubitemid 24163469)
202. Jorga KM, Kroodsma JM, Fotteler B, et al. Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites. Clin Pharmacol Ther 1998;63:646-54 (Pubitemid 28327892)
203. Lautala P, Ethell BT, Taskinen J, et al. The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos 2000;28:1385-9
204. Smith KS, Smith PL, Heady TN, et al. In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. Chem Res Toxicol 2003;16:123-8 (Pubitemid 36245861)
205. Borges N. Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy. Expert Opin Drug Saf 2005;4:69-73