Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives

Clinical Pharmacokinetics

Volumn 43, Issue 14, 2004, Pages 983-1013

  Lötsch, Jörn ^a   Skarke, Carsten ^a   Liefhold, Jürgen ^b   Geisslinger, Gerd ^a  

^a GOETHE UNIVERSITY   (Germany)

^b MUNDIPHARMA GMBH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALFENTANIL; BUPRENORPHINE; CODEINE; CODEINE 6 GLUCURONIDE; CYTOCHROME P450 2D6; DEBRISOQUINE; DEXTROMETHORPHAN; DEXTROPROPOXYPHENE; DIGOXIN; DIHYDROCODEINE; DIHYDROMORPHINE; DRUG METABOLITE; ETHYLMORPHINE; FENTANYL; FEXOFENADINE; GLUCURONOSYLTRANSFERASE; HYDROCODONE; METHADONE; MORPHINE; MORPHINE 6 GLUCURONIDE; MU OPIATE RECEPTOR; NORCODEINE; O NORTRAMADOL; OPIATE; OPIATE RECEPTOR; OXYCODONE; QUINIDINE; SPARTEINE; TRAMADOL; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALLELE; ANALGESIA; CLINICAL TRIAL; DIZZINESS; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG GLUCURONIDATION; DRUG POTENCY; DRUG RESPONSE; DRUG TRANSFORMATION; ENZYME INACTIVATION; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME SUBSTRATE; EPIGASTRIC PAIN; EUPHORIA; GENE FUNCTION; GENE MUTATION; HUMAN; MIOSIS; PHARMACOGENETICS; PRIORITY JOURNAL; PSYCHOMOTOR DISORDER; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STEADY STATE; VISUAL DISORDER;

ANALGESICS, OPIOID; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; GLUCURONOSYLTRANSFERASE; HUMANS; PAIN; PHARMACOGENETICS; POLYMORPHISM, GENETIC;

EID: 10044297116     PISSN: 03125963     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003088-200443140-00003     Document Type: Review

References (332)

1. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409 (6822): 860-921
2. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001; 291 (5507): 1304-51
3. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995; 332 (25): 1685-90
4. Ohara H, Miyabe Y, Deyashiki Y, et al. Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver. Biochem Pharmacol 1995; 50 (2): 221-7
5. Yamano S, Ichinose F, Todaka T, et al. Purification and characterization of two major forms of naloxone reductase from rabbit liver cytosol, new members of aldo-keto reductase superfamily. Biol Pharm Bull 1999; 22 (10): 1038-46
6. Yamano S, Nakamoto N, Toki S. Purification and characterization of rat liver naloxone reductase that is identical to 3α-hydroxysteroid dehydrogenase. Xenobiotica 1999; 29 (9): 917-30
7. Eichelbaum M. Polymorphic drug oxidation in humans. Fed Proc 1984; 43 (8): 2298-302
8. Liu Z, Mortimer O, Smith CA, et al. Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism. Br J Clin Pharmacol 1995; 39 (1): 77-80
9. Flockhart DA. Drug interactions: cytochrome P450 system [online]. Available from URL: http://medicine.iupui.edu/flockhart [Accesssed 2004 Aug 17]
10. Gough AC, Smith CA, Howell SM, et al. Localization of the CYP2D gene locus to human chromosome 22q13.1 by polymerase chain reaction, in situ hybridization, and linkage analysis. Genomics 1993; 15 (2): 430-2
11. Kimura S, Umeno M, Skoda RC, et al. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 1989; 45 (6): 889-904
12. Murphy MP, Beaman ME, Clark LS, et al. Prospective CYP2D6 genotyping as an exclusion criterion for enrollment of a phase III clinical trial. Pharmacogenetics 2000; 10 (7): 583-90
13. Griese EU, Zanger UM, Brudermanns U, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998; 8 (1): 15-26
14. Katoh T, Higashi K. Ethnic differences of the primary gene defect at the cytochrome P-450 2D6. J UOEH 1992; 14 (3): 205-9
15. Gaedigk A, Bradford LD, Marcucci KA, et al. Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther 2002; 72 (1): 76-89
16. Ji L, Pan S, Marti-Jaun J, et al. Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 2002; 48 (7): 983-8
17. Johansson I, Oscarson M, Yue QY, et al. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46 (3): 452-9
18. Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 1979; 16 (3): 183-7
19. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; II (8038): 584-6
20. Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51 (4): 388-97
21. Lou YC, Ying L, Bertilsson L, et al. Low frequency of slow debrisoquine hydroxylation in a native Chinese population. Lancet 1987; II (8563): 852-3
22. Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38 (4): 402-8
23. Ishizaki T, Eichelbaum M, Horai Y, et al. Evidence for polymorphic oxidation of sparteine in Japanese subjects. Br J Clin Pharmacol 1987; 23 (4): 482-5
24. Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci U S A 1993; 90 (24): 11825-9
25. Dahl ML, Johansson I, Bertilsson L, et al. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274 (1): 516-20
26. Ingelman-Sundberg M. Duplication, multiduplication, and amplification of genes encoding drug-metabolizing enzymes: evolutionary, toxicological, and clinical pharmacological aspects. Drug Metab Rev 1999; 31 (2): 449-59
27. Lovlie R, Daly AK, Matre GE, et al. Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism? Pharmacogenetics 2001; 11 (1): 45-55
28. Bathum L, Johansson I, Ingelman-Sundberg M, et al. Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction. Pharmacogenetics 1998; 8 (2): 119-23
29. Lovlie R, Daly AK, Molven A, et al. Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Lett 1996 Aug 19; 392 (1): 30-4
30. Human Cytochrome P450 Allele Nomenclature Committee. Nomenclature files for human cytochrome P450 alleles [online]. Available from URL: http://www.imm.ki.se/CYPalleles/ [Accesssed 2004 Aug 17]
31. Bertilsson L, Dahl ML, Dalen P, et al. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53 (2): 111-22
32. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29 (3): 192-209
33. Mignat C, Wille U, Ziegler A. Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci 1995; 56 (10): 793-9
34. Sindrup SH, Brosen K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 1995; 5 (6): 335-46
35. Yue QY, Svensson JO, Alm C, et al. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 1989; 28 (6): 639-45
36. Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet 1988; II (8616); 914-5
37. Yue QY, Hasselström J, Svensson JO, et al. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31 (6): 635-42
38. Chen ZR, Irvine RJ, Bochner F, et al. Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia. Life Sci 1990; 46: 1067-74
39. Sindrup SH, Arendt-Nielsen L, Brosen K, et al. The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol 1992; 42 (6): 587-91
40. Sindrup SH, Hofmann U, Asmussen J, et al. Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake. Eur J Clin Pharmacol 1996; 49 (6): 503-9
41. Sindrup SH, Brosen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1990; 48 (6): 686-93
42. Caraco Y, Sheller J, Wood AJ. Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects. J Pharmacol Exp Ther 1999; 290 (1): 413-22
43. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278 (3): 1165-74
44. Desmeules J, Gascon MP, Dayer P, et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41: 23-6
45. Dalen P, Frengell C, Dahl ML, et al. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 1997; 19 (5): 543-4
46. Hasselstrom J, Yue QY, Sawe J. The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 1997; 53 (2): 145-8
47. Poulsen L, Brosen K, Arendt-Nielsen L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51 (3-4): 289-95
48. Mikus G, Trausch B, Rodewald C, et al. Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype. Clin Pharmacol Ther 1997; 61 (4): 459-66
49. Poulsen L, Riishede L, Brosen K, et al. Codeine in postoperative pain: study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol 1998; 54 (6): 451-4
50. Persson K, Sjostrom S, Sigurdardottir I, et al. Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan. Br J Clin Pharmacol 1995; 39 (2): 182-6
51. Romach MK, Otton SV, Somer G, et al. Cytochrome P450 2D6 and treatment of codeine dependence. J Clin Psychopharmacol 2000; 20 (1): 43-5
52. Kathiramalainathan K, Kaplan HL, Romach MK, et al. Inhibition of cytochrome P450 2D6 modifies codeine abuse liability. J Clin Psychopharmacol 2000; 20 (4): 435-44
53. Eckhardt K, Li S, Ammon S, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998; 76 (1-2): 27-33
54. Moore A, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics. Pain 1996; 66 (2-3): 229-37
55. McQuay HJ, Moore RA, Eccleston C, et al. Systematic review of outpatient services for chronic pain control. Health Technol Assess 1997; 1 (6): 1-135
56. Rogers JF, Findlay JW, Hull JH, et al. Codeine disposition in smokers and nonsmokers. Clin Pharmacol Ther 1982; 32 (2): 218-27
57. Quiding H, Lundqvist G, Boreus LO, et al. Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery. Eur J Clin Pharmacol 1993; 44: 319-23
58. Vree TB, van Dongen RT, Koopman-Kimenai PM. Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Pract 2000; 54 (6): 395-8
59. Srinivasan V, Wielbo D, Simpkins J, et al. Analgesic and immunomodulatory effects of codeine and codeine 6-glucuronide. Pharm Res 1996; 13 (2): 296-300
60. Skarke C, Darimont J, Schmidt H, et al. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003; 73 (1): 107-21
61. Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362 (2): 116-21
62. Lai J, Ma SW, Porreca F, et al. Tramadol, M1 metabolite and enantiomer affinities for cloned human opioid receptors expressed in transfected HN9.10 neuroblastoma cells. Eur J Pharmacol 1996; 316 (2-3): 369-72
63. Paar WD, Poche S, Gerloff J, et al. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997; 53 (3-4): 235-9
64. Abdel-Rahman SM, Leeder JS, Wilson JT, et al. Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol 2002; 42 (1): 24-9
65. Ogunleye DS. Investigation of racial variations in the metabolism of tramadol. Eur J Drug Metab Pharmacokinet 2001; 26 (1-2): 95-8
66. Wilier JC. Studies on pain: effects of morphine on a spinal nociceptive flexion reflex and related pain sensation in man. Brain Res 1985; 331: 105-14
67. Collart L, Luthy C, Favario-Constantin C, et al. Duality of the analgesic effect of tramadol in humans [in French]. Schweiz Med Wochenschr 1993; 123 (47): 2241-3
68. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60 (6): 636-44
69. Driessen B, Reimann W. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 1992; 105 (1): 147-51
70. Driessen B, Reimann W, Giertz H. Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 1993; 108 (3): 806-11
71. Raffa RB, Friderichs E, Reimann W, et al. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther 1992; 260 (1); 275-85
72. Schmidt H, Vormfelde SV, Klinder K, et al. Affinities of dihydrocodeine and its metabolites to opioid receptors. Pharmacol Toxicol 2002; 91 (2): 57-63
73. Fromm MF, Hofmann U, Griese EU, et al. Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 1995; 58 (4): 374-82
74. Wilder-Smith CH, Hufschmid E, Thormann W. The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine: a cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 1998; 45 (6): 575-81
75. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998; 64 (6); 603-11
76. Otton SV, Schadel M, Cheung SW, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 1993; 54 (5); 463-72
77. Chen ZR, Irvine RJ, Somogyi AA, et al. μ-Receptor binding of some commonly used opioids and their metabolites. Life Sci 1991; 48: 2165-71
78. Kaplan HL, Busto UE, Baylon GJ, et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther 1997; 281 (1): 103-8
79. Begre S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 2002; 22 (2): 211-5
80. Eap CB, Broly F, Mino A, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol 2001; 21 (2): 229-34
81. Iribarne C, Dreano Y, Bardou LG, et al. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology 1997; 117 (1): 13-23
82. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy 1999; 19 (4): 471-2
83. Geletko SM, Erickson AD. Decreased methadone effect after ritonavir initiation. Pharmacotherapy 2000; 20 (1): 93-4
84. Holmes VF. Rifampin-induced methadone withdrawal in AIDS. J Clin Psychopharmacol 1990; 10 (6): 443-4
85. Bending MR, Skacel PO. Rifampicin and methadone withdrawal [letter]. Lancet 1977; I (8023): 1211
86. Iribarne C, Berthou F, Baird S, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996; 9 (2): 365-73
87. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 2002; 41 (14): 1153-93
88. Kobayashi K, Yamamoto T, Chiba K, et al. Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos 1998; 26 (8): 818-21
89. Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes: role of CYP3A4. Drug Metab Dispos 1996; 24 (9): 932-9
90. Kharasch ED, Thummel KE. Human alfentanil metabolism by cytochrome P450 3A3/4: an explanation for the interindividual variability in alfentanil clearance? Anesth Analg 1993; 76 (5): 1033-9
91. Phimmasone S, Kharasch ED. A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther 2001; 70 (6): 505-17
92. Palkama VJ, Neuvonen PJ, Olkkola KT. The CYP 3A4 inhibitor itraconazole has no effect on the pharmacokinetics of i.v. fentanyl. Br J Anaesth 1998; 81 (4): 598-600
93. Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1999; 91 (3): 681-5
94. Gellner K, Eiselt R, Mustert E, et al. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 2001; 11 (2): 111-21
95. Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 2000; 67 (1): 48-56
96. Aoyama T, Yamano S, Waxman DJ, et al. Cytochrome P-450 hPCN3, a novel cytochrome P-450 III-A gene product that is differentially expressed in adult human liver: cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 1989; 264 (18): 10388-95
97. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27 (4): 383-91
98. Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6 β-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251: 477-83
99. Coffman BL, Rios GR, King CD, et al. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997; 25 (1): 1-4
100. de Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36 (6): 439-52
101. Green MD, King CD, Mojarrabi B, et al. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase IA3. Drug Metab Dispos 1998; 26 (6): 507-12
102. Kirkwood LC, Nation RL, Somogyi AA. Glucuronidation of dihydrocodeine by human liver microsomes and the effect of inhibitors. Clin Exp Pharmacol Physiol 1998; 25 (3-4): 266-70
103. Ritter JK, Sheen YY, Owens IS. Cloning and expression of human liver UDP-glucuronosyltransferase in COS-1 cells: 3,4-catechol estrogens and estriol as primary substrates. J Biol Chem 1990; 265 (14): 7900-6
104. Bhasker CR, McKinnon W, Stone A, et al. Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 2000; 10 (8): 679-85
105. Innocenti F, Iyer L, Ramirez J, et al. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metab Dispos 2001; 29 (5): 686-92
106. Holthe M, Rakvag TN, Klepstad P, et al. Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 2003; 3 (1): 17-26
107. Coffman BL, King CD, Rios GR, et al. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y (268) and UGT2B7H (268). Drug Metab Dispos 1998; 26 (1): 73-7
108. Jin C, Miners JO, Lillywhite KJ, et al. Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate- glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther 1993; 264 (1): 475-9
109. Holthe M, Klepstad P, Zahlsen K, et al. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002; 58 (5): 353-6
110. Cepeda MS, Farrar JT, Roa JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2001; 70 (4): 351-61
111. Yue QY, Svensson JO, Sjoqvist F, et al. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31 (6): 643-7
112. Nishimura TG, Jackson SH, Cohen SN. Prolongation of morphine anaesthesia in a patient with Gilbert's disease: report of a case. Can Anaesth Soc J 1973; 20 (5): 709-12
113. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333 (18): 1171-5
114. Burchell B, Hume R. Molecular genetic basis of Gilbert's syndrome. J Gastroenterol Hepatol 1999; 14 (10): 960-6
115. Skarke C, Schmidt H, Geisslinger G, et al. Pharmacokinetics of morphine are not altered in persons with Gilbert's syndrome. Br J Clin Pharmacol 2003; 56 (2): 228-31
116. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455 (1): 152-62
117. King M, Su W, Chang A, et al. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci 2001; 4 (3): 268-74
118. Wandel C, Kim R, Wood M, et al. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 2002; 96 (4): 913-20
119. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000; 92 (5): 1392-9
120. Huwyler J, Drewe J, Klusemann C, et al. Evidence for P-glycoprotein- modulated penetration of morphine-6- glucuronide into brain capillary endothelium. Br J Pharmacol 1996; 118 (8): 1879-85
121. Lötsch J, Tegeder I, Angst MS, et al. Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test. Life Sci 2000; 66 (24): 2393-403
122. Lötsch J, Schmidt R, Vetter G, et al. Increased CNS uptake and enhanced antinociception of rnorphine-6-glucuronide in rats after inhibition of P-glycoprotein. J Neurochem 2002; 83 (2); 241-8
123. Drewe J, Ball HA, Beglinger C, et al. Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol 2000; 50 (3); 237-46
124. Sadeque AJ, Wandel C, He H, et al. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 2000; 68 (3): 231-7
125. Ueda K, Clark DP, Chen CJ, et al. The human multidrug resistance (MDR1) gene: cDNA cloning and transcription initiation. J Biol Chem 1987; 262 (2): 505-8
126. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 2000; 97 (7): 3473-8
127. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001; 69 (3): 169-74
128. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 2001; 6 (16): 835-9
129. Sakaeda T, Nakamura T, Okumura K. MDR1 genotype-related pharmacokinetics and pharmacodynamics. Biol Pharm Bull 2002; 25 (11): 1391-400
130. Schwab M, Eichelbaum M, Fromm MF. Generic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 2003; 43: 285-307
131. Ito S, Ieiri I, Tanabe M, et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 2001; 11 (2): 175-84
132. Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 2001; 297 (3): 1137-43
133. Tang K, Ngoi SM, Gwee PC, et al. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 2002; 12 (6): 437-50
134. Siegmund W, Ludwig K, Giessmann T, et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 2002; 72 (5): 572-83
135. 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 (3): 191-6
136. Schaeffeler E, Eichelbaum M, Brinkmann U, et al. Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 2001; 358 (9279): 383-4
137. Hitzl M, Drescher S, van der KH, et al. The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics 2001; 11 (4): 293-8
138. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70 (2): 189-99
139. Goto M, Masuda S, Saito H, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3 A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 2002; 12 (6): 451-7
140. Ameyaw MM, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001; 11 (3): 217-21
141. Nauck M, Stein U, von Karger S, et al. Rapid detection of the C3435T polymorphism of multidrug resistance gene 1 using fluorogenic hybridization probes. Clin Chem 2000; 46 (12): 1995-7
142. Min DI, Ellingrod VL. C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2002; 24 (3): 400-4
143. Darimont J, Skarke C, Grösch S, et al. Simple detection of single nucleotide polymorphisms C3935T of the MDR-1 gene and A1186 of the OPRM1 gene and allele frequencies among Frankfurt medical studies [abstract]. Naunyn Schmiedebergs Arch Pharmacol 2002; 365 Suppl. 1: R116
144. Wada M, Toh S, Taniguchi K, et al. Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum Mol Genet 1998; 7 (2): 203-7
145. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 1997; 25 (6): 1539-42
146. Mor-Cohen R, Zivelin A, Rosenberg N, et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 2001; 276 (40): 36923-30
147. Tirana RG, Leake BF, Merino G, et al. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 2001; 276 (38): 35669-75
148. Drescher S, Schaeffeler E, Hitzl M, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002; 53 (5): 526-34
149. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002; 359 (9300): 30-6
150. Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 2001; 18 (10): 1400-4
151. Kimchi-Sarfaty C, Gribar JJ, Gottesman MM. Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol Pharmacol 2002; 62 (1): 1-6
152. Moriya Y, Nakamura T, Horinouchi M, et al. Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects. Biol Pharm Bull 2002; 25 (10): 1356-9
153. Kurata Y, Ieiri I, Kimura M, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 2002; 72 (2): 209-19
154. Johne A, Kopke K, Gerloff T, et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 2002; 72 (5): 584-94
155. Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258 (5088): 1650-4
156. Taniguchi K, Wada M, Kohno K, et al. A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res 1996; 56 (18): 4124-9
157. Konig J, Nies AT, Cui Y, et al. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1999; 1461 (2): 377-94
158. Flens MJ, Zaman GJ, van der Valk P, et al. Tissue distribution of the multidrug resistance protein. Am J Pathol 1996; 148 (4): 1237-47
159. Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins. Biochim Biophys Acta 1999; 1461 (2): 237-62
160. Borst P, Evers R, Kool M, et al. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92 (16): 1295-302
161. Müller M. Human ATP-binding cassette transporters [online]. Available from URL: http://nutrigene.4t.com/humanabc.htm [Accesssed 2004 Aug 17]
162. Sweet DH, Bush KT, Nigam SK. The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol 2001; 281 (2): F197-205
163. Tamai I, Nozawa T, Koshida M, et al. Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res 2001; 18 (9): 1262-9
164. Race JE, Grassl SM, Williams WJ, et al. Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3). Biochem Biophys Res Commun 1999; 255 (2): 508-14
165. Kullak-Ublick GA, Hagenbuch B, Stieger B, et al. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 1995; 109 (4): 1274-82
166. Kusuhara H, Sugiyama Y. Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J Control Release 2002; 78 (1-3): 43-54
167. Gao B, Hagenbuch B, Kullak-Ublick GA, et al. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 2000; 294 (1): 73-9
168. Haga S, Hinoshita E, Ikezaki K, et al. Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma. Jpn J Cancer Res 2001; 92(2): 211-9
169. Sugiyama Y, Kusuhara H, Suzuki H. Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain. J Control Release 1999; 62 (1-2): 179-86
170. Morin RA, Lyness WH. Potentiation of morphine analgesia after pretreatment with probenecid or sulfinpyrazone. Pharmacol Biochem Behav 1983; 18 (6): 885-9
171. Leslie EM, Ito K, Upadhyaya P, et al. Transport of the β-O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1): requirement for glutathione or a non-sulfur-containing analog. J Biol Chem 2001; 276 (30): 27846-54
172. Zelcer N, Saeki T, Reid G, et al. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem 2001; 276 (49): 46400-7
173. Sugiyama D, Kusuhara H, Shitara Y, et al. Characterization of the efflux transport of 17β-estradiol-D-17β-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther 2001; 298 (1): 316-22
174. Huang L, Smit JW, Meijer DK, et al. MRP2 is essential for estradiol-17β (β-D-glucuronide)-induced cholestasis in rats. Hepatology 2000; 32 (1): 66-72
175. Keppler D, Leier I, Jedlitschky G. Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biol Chem 1997; 378 (8): 787-91
176. Lötsch J, Schmidt R, Vetter G, et al. The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats. Neurosci Lett 2002; 329 (2): 145-8
177. Xie R, Bouw MR, Hammarlund-Udenaes M. Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport. Br J Pharmacol 2000; 131 (8): 1784-92
178. Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment of liver cells: new clinico-pathologic entity with report of 12 cases. Medicine 1954; 33: 155-97
179. Saito S, Iida A, Sekine A, et al. Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/MRP/CFTR). J Hum Genet 2002; 47 (4): 147-71
180. Iida A, Saito S, Sekine A, et al. Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH: ubiquinone oxidoreductase flavoproteins. J Hum Genet 2001; 46 (11): 668-83
181. Wang JB, Johnson PS, Persico AM, et al. Human μ opiate receptor: cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett 1994; 338 (2): 217-22
182. LaForge KS, Yuferov V, Kreek MJ. Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol 2000; 410 (2-3): 249-68
183. Befort K, Filliol D, Decaillot FM, et al. A single-nucleotide polymorphic mutation in the human μ-opioid receptor severely impairs receptor signaling. J Biol Chem 2001; 276 (5): 3130-7
184. Hoehe MR, Kopke K, Wendel B, et al. Sequence variability and candidate gene analysis in complex disease: association of μ opioid receptor gene variation with substance dependence. Hum Mol Genet 2000; 9 (19): 2895-908
185. Koch T, Kroslak T, Averbeck M, et al. Allelic variation S268P of the human μ-opioid receptor affects both desensitization and G protein coupling. Mol Pharmacol 2000; 58 (2): 328-34
186. Wang D, Quillan JM, Winans K, et al. Single nucleotide polymorphisms in the human μ opioid receptor gene alter basal G protein coupling and calmodulin binding. J Biol Chem 2001; 276 (37): 34624-30
187. Uhl GR, Sora I, Wang Z. The μ opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci U S A 1999; 96 (14): 7752-5
188. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human μ opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998; 95 (16): 9608-13
189. Li T, Liu X, Zhu HZ, et al. Association analysis of polymorphism in the μ-opioid gene and heroin abuse in Chinese subjects. Addict Biol 2000; 5: 181-6
190. Gelernter J, Kranzler H, Cubells J. Genetics of two μ opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatry 1999; 4 (5): 476-83
191. Town T, Schinka J, Tan J, et al. The opioid receptor system and alcoholism: a genetic perspective. Eur J Pharmacol 2000; 410 (2-3): 243-8
192. Town T, Abdullah L, Crawford F, et al. Association of a functional μ-opioid receptor allele (+118A) with alcohol dependency. Am J Med Genet 1999; 88 (5): 458-61
193. Bergen AW, Kokoszka J, Peterson R, et al. μ-Opioid receptor gene variants: lack of association with alcohol dependence. Mol Psychiatry 1997; 2 (6): 490-4
194. Szeto CY, Tang NL, Lee DT, et al. Association between μ opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 2001; 12 (6): 1103-6
195. Schinka JA, Town T, Abdullah L, et al. A functional polymorphism within the μ-opioid receptor gene and risk for abuse of alcohol and other substances. Mol Psychiatry 2002; 7 (2): 224-8
196. Ohmori O, Shinkai T, Hori H, et al. Polymorphisms of μ and δ opioid receptor genes and tardive dyskinesia in patients with schizophrenia. Schizophr Res 2001; 52 (1-2): 137-8
197. Lötsch J, Skarke C, Grösch S, et al. The polymorphism A118G of the human μ-opioid receptor gene decreases the clinical activity of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002; 12 (1): 3-9
198. Tan EC, Tan CH, Karupathivan U, et al. μ-Opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport 2003; 14 (4): 569-72
199. Shi J, Hui L, Xu Y, et al. Sequence variations in the μ-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 2002; 19 (4): 459-60
200. Mayer P, Rochlitz H, Rauch E, et al. Association between a δ opioid receptor gene polymorphism and heroin dependence in man. Neuroreport 1997; 8 (11): 2547-50
201. Gelernter J, Kranzler HR. Variant detection at the δ opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence. Hum Genet 2000; 107 (1): 86-8
202. Beyer A, Koch T, Höllt V. A118G polymorphism does not alter the ligand binding and activity of the human μ-opioid receptor [abstract]. Naunyn Schmiedebergs Arch Pharmacol 2003; 367 Suppl. 1: R17
203. Angst MS, Bührer M, Lötsch J. Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action. Anesthesiology 2000; 92 (5): 1473-6
204. Hasselström J, Berg U, Lofgren A, et al. Long lasting respiratory depression induced by morphine-6-glucuronide? Br J Clin Pharmacol 1989; 27: 515-8
205. Bodd E, Jacobsen D, Lund E, et al. Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Hum Exp Toxicol 1990; 9: 317-21
206. Caraco Y, Maroz Y, Davidson E. Variability in alfentanil analgesia maybe attributed to polymorphism in the μ-opioid receptor gene [abstract]. Clin Pharmacol Ther 2001; 69 (2): 63
207. Hirota T, Ieiri I, Takane H, et al. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos 2003; 31 (5); 677-80
208. Wand GS, McCaul M, Yang X, et al. The μ-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 2002; 26 (1): 106-14
209. Berrettini WH, Hoehe MR, Ferraro TN, et al. Human μ opioid receptor gene polymorphisms and vulnerability to substance abuse. Addict Biol 1997; 2 (3): 303-8
210. Franke P, Wang T, Nothen MM, et al. Nonreplication of association between μ-opioid-receptor gene (OPRM1) A118G polymorphism and substance dependence. Am J Med Genet 2001; 105 (1): 114-9
211. Rossi GC, Leventhal L, Pan YX, et al. Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6β-glucuronide antinociception. J Pharmacol Exp Ther 1997; 281 (1): 109-14
212. Thompson TE, Rogan PK, Risinger JI, et al. Splice variants but not mutations of DNA polymerase β are common in bladder cancer. Cancer Res 2002; 62 (11): 3251-6
213. Beyer KS, Klauck SM, Benner A, et al. Association studies of the HOPA dodecamer duplication variant in different subtypes of autism. Am J Med Genet 2002; 114 (1): 110-5
214. De Souza EB, Schmidt WK, Kuhar MJ. Nalbuphine: an autoradiographic opioid receptor binding profile in the central nervous system of an agonist/antagonist analgesic. J Pharmacol Exp Ther 1988; 244 (1): 391-402
215. Nozaki M, Niwa M, Hasegawa J, et al. Opioid receptor interactions of butorphanol, a narcotic antagonist analgesic, and its metabolites [in Japanese]. Nippon Yakurigaku Zasshi 1983; 82 (6); 443-50
216. Goldstein A, Naidu A. Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol Pharmacol 1989; 36 (2): 265-72
217. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be κ-opioid receptor mediated. Pain 1997; 73 (2): 151-7
218. Monory K, Greiner E, Sartania N, et al. Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci 1999; 64 (22): 2011-20
219. Yasuda K, Espinosa III R, Takeda J, et al. Localization of the κ opioid receptor gene to human chromosome band 8q11.2. Genomics 1994; 19 (3): 596-7
220. Simonin F, Gaveriaux-Ruff C, Befort K, et al. κ-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA 1995; 92 (15): 7006-10
221. Franke P, Nothen MM, Wang T, et al. Human δ-opioid receptor gene and susceptibility to heroin and alcohol dependence. Am J Med Genet 1999; 88 (5): 462-4
222. Bzdega T, Chin H, Kim H, et al. Regional expression and chromosomal localization of the δ opiate receptor gene. Proc Natl Acad Sci U S A 1993; 90 (20): 9305-9
223. Simonin F, Befort K, Gaveriaux-Ruff C, et al. The human δ-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain. Mol Pharmacol 1994; 46 (6): 1015-21
224. Bergen AW, Van Den Bree MB, Yeager M, et al. Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin ID and δ opioid receptor loci exhibit significant association to anorexia nervosa. Mol Psychiatry 2003; 8 (4): 397-406
225. Halfpenny DM, Callado LF, Hopwood SE, et al. Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry. Br J Anaesth 1999; 83 (6): 909-15
226. Oliva P, Aurilio C, Massimo F, et al. The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 2002; 445 (3): 179-85
227. Garrido MJ, Valle M, Campanero MA, et al. Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther 2000; 295 (1): 352-9
228. Gobbi M, Mennini T. Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser. Eur J Pharmacol 1999; 370 (1): 23-6
229. Raffa RB, Friderichs E, Reimann W, et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993; 267 (1): 331-40
230. Bamigbade TA, Davidson C, Langford RM, et al. Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997; 79 (3): 352-6
231. Arcioni R, della Rocca M, Romano S, et al. Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg 2002; 94 (6): 1553-7
232. De Witte JL, Schoenmaekers B, Sessler DI, et al. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001; 92 (5): 1319-21
233. Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, et al. Pindolol, a β-adrenoceptor blocker/5-hydroxytryptamine (1A/1B) antagonist, enhances the analgesic effect of tramadol. Pain 2000; 88 (2): 119-24
234. Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995; 274 (3): 1263-70
235. Nemmani KV, Gullapalli S, Ramarao P. Potentiation of κ-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine. Pharmacol Biochem Behav 2001; 69 (1-2): 189-93
236. Nayebi AR, Hassanpour M, Rezazadeh H. Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats. J Pharm Pharmacol 2001; 53 (2): 219-25
237. Luger TJ, Lorenz IH, Grabner-Weiss C, et al. Effect of fluvoxamine on sufentanil antinociception and tolerance under chronic intravenous infusion in rats. Pharmacol Toxicol 1999; 85 (6): 263-8
238. Wang YX, Bowersox SS, Pettus M, et al. Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy. J Pharmacol Exp Ther 1999; 291 (3): 1008-16
239. Tulunay FC, Yano I, Takemori AE. The effect of biogenic amine modifiers on morphine analgesia and its antagonism by naloxone. Eur J Pharmacol 1976; 35: 285-92
240. Tenen SS. Antagonism of the analgesic effect of morphine and other drugs by p-chlorophenylalanine, a serotonin depletor. Psychopharmacologia 1968; 12: 278-85
241. Tenen SS. The effects of p-chlorophenylalanine, a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychopharmacologia 1967; 10: 204-19
242. Ho IK, Brase DA, Loh HH, et al. Influence of L-tryptophan on morphine analgesia, tolerance and physical dependence. J Pharmacol Exp Ther 1975; 193: 35-43
243. Abbott FV, Young SN. Effect of 5-hydroxytryptamine precursors on morphine analgesia in the formalin test. Pharmacol Biochem Behav 1989; 31: 855-60
244. Coda BA, Hill HF, Schaffer RL, et al. Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions. Pain 1993; 52 (1): 85-91
245. Erjavec MK, Coda BA, Nguyen Q, et al. Morphine-fluoxetine interactions in healthy volunteers: analgesia and side effects. J Clin Pharmacol 2000; 40 (11): 1286-95
246. Gordon NC, Heller PH, Gear RW, et al. Interactions between fluoxetine and opiate analgesia for postoperative dental pain. Pain 1994; 58: 85-8
247. Abbott FV, Etienne P, Franklin KB, et al. Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans. Psychopharmacology (Berl) 1992; 108: 60-6
248. Hosobuchi Y, Lamb S, Baskin D. Tryptophan loading may reverse tolerance to opiate analgesics in humans: a preliminary report. Pain 1980; 9: 161-9
249. Staner L, Uyanik G, Correa H, et al. A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients. Am J Med Genet 2002; 114 (5): 553-7
250. Ebstein RP, Benjamin J, Belmaker RH. Personality and polymorphisms of genes involved in aminergic neurotransmission. Eur J Pharmacol 2000; 410 (2-3): 205-14
251. Arinami T, Ishiguro H, Onaivi ES. Polymorphisms in genes involved in neurotransmission in relation to smoking. Eur J Pharmacol 2000; 410 (2-3): 215-26
252. Weizman A, Weizman R. Serotonin transporter polymorphism and response to SSRIs in major depression and relevance to anxiety disorders and substance abuse. Pharmacogenomics 2000; 1 (3): 335-41
253. Blakely RD. Physiological genomics of antidepressant targets: keeping the periphery in mind. J Neurosci 2001; 21 (21): 8319-23
254. Catalano M. Functionally gene-linked polymorphic regions and genetically controlled neurotransmitters metabolism. Eur Neuropsychopharmacol 2001; 11 (6): 431-9
255. Du L, Faludi G, Palkovits M, et al. Serotonergic genes and suicidality. Crisis 2001; 22 (2): 54-60
256. Arranz MJ, Munro J, Owen MJ, et al. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 1998; 3 (1): 61-6
257. Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995; 346 (8970): 281-2
258. Arranz MJ, Collier DA, Munro J, et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett 1996; 217 (2-3): 177-8
259. Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359 (9323): 2086-7
260. Ramamoorthy S, Bauman AL, Moore KR, et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1993; 90 (6): 2542-6
261. Herken H, Erdal E, Mutlu N, et al. Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. Am J Orthod Dentofacial Orthop 2001; 120 (3): 308-13
262. Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66 (6): 2621-4
263. Offenbaecher M, Bondy B, de Jonge S, et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum 1999; 42 (11): 2482-8
264. Sparkes RS, Lan N, Klisak I, et al. Assignment of a serotonin 5HT-2 receptor gene (HTR2) to human chromosome 13q14-q21 and mouse chromosome 14. Genomics 1991; 9 (3): 461-5
265. Bondy B, Spaeth M, Offenbaecher M, et al. The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 1999; 6 (5): 433-9
266. Lubov U, Alfimova M, Golimbet V. Pain thresholds and serotonin receptor 2A gene polymorphism in schizophrenic families [abstract]. Eur Psychiatry 2002; 17 Suppl. 1: 172
267. Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996; 41 (1): 7-12
268. Small KM, Liggett SB. Identification and functional characterization of α (2)-adrenoceptor polymorphisms. Trends Pharmacol Sci 2001; 22 (9): 471-7
269. Pacholczyk T, Blakely RD, Amara SG. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 1991; 350 (6316): 350-4
270. German AL, Elliott KJ, Inturrisi CE. The d- and 1-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997; 223 (1): 5-8
271. Choi DW, Viseskul V. Opioids and non-opioid enantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons. Eur J Pharmacol 1988; 155 (1-2): 27-35
272. Bulka A, Wiesenfeld-Hallin Z, Xu XJ. Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan. Brain Res 2002; 942 (1-2): 95-100
273. Oxenham D, Farrer K. Methadone: opioid, N-methyl-D-aspartate antagonist or both [letter]. Palliat Med 1998; 12 (4): 302
274. Yamakura T, Sakimura K, Shimoji K. N-methyl-D-aspartate receptor channel block by meperidine is dependent on extracellular pH. Anesth Analg 2000; 90 (4): 928-32
275. Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995; 187 (3): 165-8
276. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 1999; 289 (2): 1048-53
277. Chizh BA, Schlutz H, Scheede M, et al. The N-methyl-D-aspartate antagonistic and opioid components of d-methadone antinociception in the rat spinal cord. Neurosci Lett 2000; 296 (2-3): 117-20
278. Stringer M, Makin MK, Miles J, et al. d-Morphine, but not 1-morphine, has low micromolar affinity for the non-competitive N-methyl-D-aspartate site in rat forebrain: possible clinical implications for the management of neuropathic pain. Neurosci Lett 2000; 295 (1-2): 21-4
279. Ebert B, Thorkildsen C, Andersen S, et al. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol 1998; 56 (5): 553-9
280. Tsai SJ, Liu HC, Liu TY, et al. Association analysis for genetic variants of the NMDA receptor 2b subunit (GRIN2B) and Parkinson's disease. J Neural Transm 2002; 109 (4): 483-8
281. Rice SR, Niu N, Berman DB, et al. Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. Mol Psychiatry 2001; 6 (3): 274-84
282. Sakurai K, Toru M, Yamakawa-Kobayashi K, et al. Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia. Neurosci Lett 2000; 296 (2-3): 168-70
283. Nishiguchi N, Shirakawa O, Ono H, et al. Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia. Am J Psychiatry 2000; 157 (8): 1329-31
284. Williams NM, Bowen T, Spurlock G, et al. Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor. Mol Psychiatry 2002; 7 (5): 508-14
285. Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 1992; 256 (5060): 1217-21
286. Ohtsuki T, Sakurai K, Dou H, et al. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 2001; 6 (2): 211-6
287. Sander T, Ostapowicz A, Samochowiec J, et al. Genetic variation of the glutamate transporter EAAT2 gene and vulnerability to alcohol dependence. Psychiatr Genet 2000; 10 (3): 103-7
288. Mogil JS, Wilson SG, Bon K, et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 1999; 80 (1-2): 67-82
289. Mogil JS, Wilson SG, Bon K, et al. Heritability of nociception II: 'types' of nociception revealed by genetic correlation analysis. Pain 1999; 80 (1-2): 83-93
290. Mogil JS. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci U S A 1999; 96 (14): 7744-51
291. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41 (12): 913-58
292. Xie HG, Kim RB, Wood AJ, et al. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 2001; 41: 815-50
293. Wood AJ. Ethnic differences in drug disposition and response. Ther Drug Monit 1998; 20 (5): 525-6
294. Llerena A, Cobaleda J, Martinez C, et al. Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype. Eur J Drug Metab Pharmacokinet 1996; 21 (2): 129-38
295. Gaedigk A. Interethnic differences of drug-metabolizing enzymes. Int J Clin Pharmacol Ther 2000; 38 (2): 61-8
296. Lemmens HJ, Bovill JG, Hennis PJ, et al. Alcohol consumption alters the pharmacodynamics of alfentanil. Anesthesiology 1989; 71 (5): 669-74
297. Harada S, Agarwal DP, Nomura F, et al. Metabolic and ethnic determinants of alcohol drinking habits and vulnerability to alcohol-related disorder. Alcohol Clin Exp Res 2001; 25 (5 Suppl. ISBRA): 71S-5S
298. Dahmani S, Dupont H, Mantz J, et al. Predictive factors of early morphine requirements in the post-anaesthesia care unit (PACU). Br J Anaesth 2001; 87 (3): 385-9
299. Faucett J, Gordon N, Levine J. Differences in postoperative pain severity among four ethnic groups. J Pain Symptom Manage 1994; 9 (6): 383-9
300. Lipton JA, Marbach JJ. Ethnicity and the pain experience. Soc Sci Med 1984; 19 (12): 1279-98
301. Greenwald HP. Interethnic differences in pain perception. Pain 1991; 44 (2): 157-63
302. Weisenberg M, Caspi Z. Cultural and educational influences on pain of childbirth. J Pain Symptom Manage 1989; 4 (1): 13-9
303. Mogil JS, Kest B. Sex differences in opioid analgesia: of mice and women. Pain Forum 1999; 8 (1): 48-50
304. Kest B, Sarton E, Dahan A. Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology 2000; 93 (2): 539-47
305. Schwartz JB. Gender differences in response to drugs: pain medications. J Gend Specif Med 1999; 2 (5): 28-30
306. Miaskowski C, Levine JD. Does opioid analgesia show a gender preference for females? Pain Forum 1999; 8: 34-44
307. Gear RW, Miaskowski C, Gordon NC, et al. The κ opioid nalbuphine produces gender- and dose-dependent analgesia and anti-analgesia in patients with postoperative pain. Pain 1999; 83 (2): 339-45
308. Gear RW, Miaskowski C, Gordon NC, et al. κ-Opioids produce significantly greater analgesia in women than in men. Nat Med 1996; 2 (11): 1248-50
309. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93 (5): 1245-54
310. Pleuvry BJ, Maddison SE. A sex difference in the effects of oral codeine and promethazine on the ventilatory response to carbon dioxide in human volunteers. Br J Clin Pharmacol 1980; 9 (2): 159-64
311. Dahan A, Sarton E, Teppema L, et al. Sex-related differences in the influence of morphine on ventilatory control in humans. Anesthesiology 1998; 88 (4): 903-13
312. Zubieta IK, Dannals RF, Frost JJ. Gender and age influences on human brain μ-opioid receptor binding measured by PET. Am J Psychiatry 1999; 156 (6): 842-8
313. Zubieta JK, Smith YR, Bueller JA, et al. Mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 2002; 22 (12): 5100-7
314. Unruh AM. Gender variations in clinical pain experience. Pain 1996; 65 (2-3): 123-67
315. Fernandez-Real JM, Penarroja G, Richart C, et al. G protein β3 gene variant, vascular function, and insulin sensitivity in type 2 diabetes. Hypertension 2003; 41 (1): 124-9
316. Stitham J, Stojanovic A, Hwa J. Impaired receptor binding and activation associated with a human prostacyclin receptor polymorphism. J Biol Chem 2002; 277 (18): 15439-44
317. Chang AC, Cochet M, Cohen SN. Structural organization of human genomic DNA encoding the propiomelanocortin peptide. Proc Natl Acad Sci U S A 1980; 77 (8): 4890-4
318. Comb M, Seeburg PH, Adelman J, et al. Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature 1982; 295 (5851): 663-6
319. Noda M, Teranishi Y, Takahashi H, et al. Isolation and structural organization of the human preproenkephalin gene. Nature 1982; 297 (5865): 431-4
320. Esapa CT, Harris PE. Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours. Eur J Endocrinol 1999; 141 (4): 409-12
321. Ulrich CM, Bigler J, Sibert J, et al. Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations. Hum Mutat 2002; 20 (5): 409-10
322. Cipollone F, Patrono C. Cyclooxygenase-2 polymorphism: putting a brake on the inflammatory response to vascular injury? Arterioscler Thromb Vasc Biol 2002; 22 (10): 1516-8
323. Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 2003; 73 (1): 122-30
324. Kanai N, Lu R, Satriano JA, et al. Identification and characterization of a prostaglandin transporter. Science 1995; 268 (5212): 866-9
325. Samad TA, Sapirstein A, Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med 2002; 8 (8): 390-6
326. Sander T, Berlin W, Ostapowicz A, et al. Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and susceptibility to idiopathic generalized epilepsy. Epilepsy Res 2000; 41 (1): 75-81
327. Wu D, Otton SV, Sproule BA, et al. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993; 35 (1): 30-4
328. Pauli-Magnus C, Rekersbrink S, Klotz U, et al. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 2001; 364 (6): 551-7
329. Perault MC, Bouquet S, Bertschy G, et al. Debrisoquine and dextromethorphan phenotyping and antidepressant treatment. Therapie 1991; 46 (1): 1-3
330. Weinbroum AA. Dextromethorphan reduces immediate and late postoperative analgesic requirements and improves patients' subjective scorings after epidural lidocaine and general anesthesia. Anesth Analg 2002; 94 (6): 1547-52
331. Ilkjaer S, Bach LF, Nielsen PA, et al. Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain 2000; 86 (1-2): 19-24
332. Henderson DJ, Withington BS, Wilson JA, et al. Perioperative dextromethorphan reduces postoperative pain after hysterectomy. Anesth Analg 1999; 89 (2): 399-402