摘要
细胞色素P4502D6(CYP2D6)是一种重要的药物代谢酶,参与临床近百种重要药物的代谢,而且对药物的代谢呈现出明显的个体差异和种族差异,这是造成临床用药个体差异的重要原因。CYP2D6是最具有基因多态性的药物代谢酶,目前已发现有七十多个变异位点。本研究拟制备基因芯片,测定中国人群CYP2D6基因多态性的分布频率,并研究不同基因型的中国健康志愿者体内曲马多和美托洛尔的代谢特点及其对两药相互作用的影响。
1.基因芯片法测定中国人群CYP2D6基因多态性
根据CYP2D6基因序列的多态性分布特点,针对在中国人群药物代谢中具有潜在作用的突变位点C188T和G4268C(CYP2D6*2和CYP2D6*10),设计寡核苷酸探针,制备寡核苷酸芯片,测定312例中国健康志愿者CYP2D6的基因型,并使用直接测序法对分型结果进行验证,探讨基因芯片技术应用于CYP2D6基因分型的可行性。结果312例中国健康志愿者中CYP2D6*2和CYP2D6*10的变异频率分别为CYP2D6*2W*10W 8.3%, *2H*10W 13.5%, *2M*10W 10.6%, *2M*10H 17.0%, *2M*10M 34.6%, *2H*10H 9.6%, *2H*10M 6.4%。对部分样本采用直接测序的方法进行进一步确证,结果完全吻合。说明本研究建立的基因芯片适用于中国人群CYP2D6基因分型研究。
2.中国人群CYP2D6基因多态性对曲马多药代动力学的影响
按照变异位点,筛选40例健康志愿者,分为四组进行试验,每组10人。第一组:CYP2D6*2W*10W,第二组:CYP2D6*2H*10W和CYP2D6*2M*10W,
Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme, which metabolizes nearly 100 drugs. CYP2D6 was first identified as the polymorphic enzyme involved in debrisoquine hydroxylation and sparteine oxidation. Currently more than 70 different alleles have been described. In this study, gene chips are created to evaluate the allelic frequency of CYP2D6 and investigate the influence of genetic polymorphism of CYP2D6 on pharmacokinetic interactions between tramadol and metoprolol in a Chinese population.
1. Screening the genetic polymorphism of CYP2D6 in a Chinese population by gene chips
According to the distributing feature of the polymorphisms in CYP2D6 gene, specially aimed to C188T and G4268C, the two mutant sites reported to have the potent effects in the drug metabolism of Chinese people, gene chips are created with a set of designed oligonuceotides probes. 312 DNA samples from Chinese healthy volunteers were genotyped and parts of samples were validated by direct sequencing. The results of these two genotyping methods are in concordance which indicates that the gene chips established in this study can be applied to screen the genotypes of CYP2D6 in a Chinese population. The allelic frequencies of CYP2D6 were 8.3% (CYP2D6*2W*10W), 13.5% (CYP2D6*2H*10W), 10.6% (CYP2D6*2M*10W),
引文
1. Evans WE, Relling MV. Pharmacogenetics: Translating functional genomics into rational therapeutics. Sciencs. 1999, 286: 487-491
2. Mark WL, Russell AP, Roland VJ. Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency. Clin Chem 1997, 43: 254-266
3. Nicholson JK, Connelly J, Lindon JC. Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Disc, 2002, 1: 153-161
4. Gennan JB, Bauman DE, Burrin DG. Metabolomics in the opening decade of the 21st century: building the roads to individualized health. J Nutr, 2004, 134 (10): 2729-2737
5. 孙忠实,朱珠. 药物代谢性相互作用研究进展. 医药世界,2004, 8:60-61
6. 孙忠实. 药物代谢与合理用药. 中国药学杂志,2001,36 (1): 60-61
7. Ulrich MZ, Joachim F, Sebastian R, Thomas S, Bernd OF, Matthias S, Michel E. Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics, 2001, 11: 573-585
8. Inger J, Eva L, Leif B, Marja-Liisa D, Folke S, Magnus IS. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci. 1993, 90:11825-11829
9. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 1996, 6: 1-42
10. Jan VD, Linda SW. Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical pharmacology. Ann Clin Biochem, 1999, 36: 722-729
11. Benny K., Adithan C. Genetic polymorphism of CYP2D6. Indian Journal of Pharmacology, 2001, 33: 147-169
12. 付良青,吴德政. 细胞色素 P4502D6 的研究进展. 中国临床药理学杂志,2000, 16 (6): 453-457
13. Oscarson M, Hidestrand M, Johannsson I, Ingelman-Sundberg M. A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme function. Mol Pharmacol, 1997, 52:1034-1040
14. http://www.imm.ki.se/CYPallele/cyp2d6.htm
15. Pedersen RS, Damkier P, Brosen K. Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther, 2005, 77: 458-467
16. Streetman, Daniel S., Bertino, et al. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes [J]. Pharmacogenetics, 2000, 10(3): 187-216
17. Magnus Ingelman-Sundberg. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. TRENDS in Pharmacological Sciences, 2004; 25(4) :193-200
18. Gao Y, Zhang Q. Polymorphisms of GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. Mutat Res 1999; 444: 441-449
19. Kubota T., Yamaura Y., Ohkawa N., et al. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol, 2000; 50, 31-34
20. Ji L, Pan SX. Genetic polymorphism of CYP2D6 in Chinese mailand. Chin Medical Journal 2002; 115 (12): 1780-1784
21. Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metabolism and Disposition, 1999, 27 (3): 385-388
22. Kenneth A.B. Genotyping and phenotyping the cytochrome P450 Enzymes. American Journal of Therapeutics, 2002; 9: 309-316
23. 文思远,王升启. 单核苷酸多态性基因分型技术原理与进展. 生物技术通讯, 2003; 14: 86-90
24. Wang JY, Sesh ES, Lee EJ. Pharmacogenetics: the molecular genetics of CYP2D6 dependent drug metablism. Ann Acad Med Singapore, 2000;29: 401-406
25. Garcia-Barcelo M, Chow LY, Chiu HF, et al. Genetic analysis of the CYP2D6 locus in a HongKong Chinese population. Clin Chem 2000; 46:18-23
26. Masato T, Takashi N, Tomoki K, Hiroshi I, Chihiro T, Akiko M, Yukiya H. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol, 2003; 59: 385-388
27. Roh H.,Chung J. Plasma concentration of haloperidol are related to CYP2D6 genotype at low but not high dose of haloperidol in Korean Schizophrenic patients. Br J Clin Pharmacol, 2001; 52: 265-272
28. Huang J, Chuang SK, Cheng CL, Lai ML. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin Pharmacol Ther 1999;65: 402–407
29. O'Meara D, Ahmadian A, Odeberg J, et al. SNP typing by apyrase-mediated allele-specific primer extension on DNA microarrays. Nucleic Acids Res 2002; 30: e75
30. Burkhardt M, Konstanze Z, Julia B, Werner S. Optimized strategy for rapid cytochrome P450
2D6 genotyping by real-time long PCR. Clinical Chemistry, 2003; 49 (10): 1624-1631
31. Iwasaki H, Ezura Y, Ishida R, et al. Accuracy of genotyping for single nucleotide polymorphisms by a microarray-based single nucleotide polymorphism typing method involving hybridization of short allele-specific oligonucleotides. DNA Res 2002; 9: 59-62
32. Kleiber J, Walter T, Haberhausen G, et al. Performance characteristics of a quantitative, homogeneous TaqMan RT-PCR test for HCV RNA. J Mol Diagn 2000; 2: 158-166
33. Huber M, Mundlein A, Dornstauder E, et al. Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays. Anal Biochem 2002; 303: 25-33
34. Chou WH, Yan FX, Doris K, et al. Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships. Clinical Chemistry, 2003; 49 (4): 542-551
35. Greer M, Bruce G, Margaret A, et al. CYP2D6 genotyping with oligonucleotide Microarrays and nortriptyline concentrations in geriatric depression. Neuropsychopharmacology, 2001; 25 (5) : 737-743
36. Olivier T, Yvon L, Jean-Michel R, Herve A, Daniele BF. Pharmacogenomics. Med Sci Monit, 2002, 8(7): 152-163
37. Chin BE, Etienne L, Pierre B, Marlyse BA, Marie-Andree Y, Gilles O, Jacques T. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics, 2003, 13(1): 39-47
38. Ozaki N. Pharmacogenetics of antipsychoatics. Nagoya J Med Sci, 2004, 67(1-2): 1-7
39. Kitada M. Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6. Int J Clin Pharmacol Res, 2003, 23(1): 31-35
40. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol, 2002, 53(2):111-122
41. Lam LC, Garcia-Barcelo MM, Ungvari GS, Tang WK, Lam VK, Kwong SL, Lau BS, Kwong PP, Waye MM, Chiu HF. Cytochrome P450 2D6 genotyping and association with tardive dyskinesia in Chinese schizophrenic patients. Pharmacopsychiatry, 2001, 34(6): 238-241
42. Lee CR, McTavish D, Sorkim EM. Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993, 46: 313-340
43. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001, 29: 1146-1155
44. Gan SH, Ismail R, Wan Adnan WA, Zulmi W, Jelliffe RW. Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms. J Clin Pharm Ther, 2004, 29(5): 455-463
45. Klotz U. Tramadol--the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain. Arzneimittelforschung. 2003, 53(10):681-687
46. Abdel-Rahman SM, Leeder JS, Wilson JT, Gaedigk A, Gotschall RR, Medve R. Concordance between tramadol and dextromethorphan parent/ metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol, 2002, 42: 24-29
47. Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A, Stuber F. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003, 105(1-2): 231-238
48. Nobilis M, Kopecky J, Kvetina J. High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma application to a bioequivalence study in humans. J Chromatogr A, 2002, 949: 11-22
49. Miguel AC, Emilio GQ, Belen S, et al. Simultaneous stereoselective analysis of tramadol and its primary phase I metabolites in plasma by liquid chromatography application to a pharmacokinetic study in humans. J Chromatogr A, 2004, 1031: 219-228
50. Yeh GC, Sheu MT, Yen CL, Wang YW, Liu CH, Ho HO. High-performance liquid chromatographic method for determination of tramadol in human plasma. J Chromatogr B, 1999, 723:247-253
51. GC Yeh, MT Sheu, CL Yen, et al. High-performance liquid chromatographic method for determination of tramadol in human plasma. J Chromatogr B, 1999, 723: 247-253
52. SH Gan, R Ismail, WA Wan Adnan, et al. Method development and validation of a high-performance liquid chromatographic method for tramadol in human plasma using liquid-liquid extraction. J Chromatogr B, 2002, 772: 123-129
53. Dalen P, Dahl M, Andersson K, Bertilsson L. Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes. Br J Clin Pharmacol. 2000,49(2):180-184
54. Rae Yuan, Soraya Madani, Xiao-xiong Wei. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metabolism and Disposition, 2002,30: 1311-1319
55. Vandel P, Haffen E, Nezelof S, Broly F, Kantelip JP, Sechter D. Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients. Hum Psychopharmacol, 2004, 19(5):293-298
56. Schwartz GL, Turner ST. Pharmacogenetics of antihypertensive drug responses. Am J Pharmacogenomics, 2004, 4(3):151-160
57. Kari L, Steven DB, Harry B, Juha R, Jutta H, Harry S, et al. Effect of the novel anxiolytic drug deramciclane on cytochrome P450 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol, 2004,59: 893-898
58. Characterization of (±)-bufuralol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6. Pharmacogenetics, 2001, 11:143-156
59. Nakamura K, Ariyoshi N, Yokoi T, Ohgiya S, Chida M, Nagashima K, Inoue K, Kodama T, Shimada N, Kamataki T. CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability. Biochem Biophys Res Commun, 2002, 293(3): 969-973
60. Albers LJ, Reist C, Vu RL. Effect of venlafaxine on imipramine metabolism. Psychiatry Res, 2000,96(3): 235-243
61. Chen B, Cai WM. Influence of CYP2D6*10B genotype on pharmacokinetics of propafenone enantiomers in Chinese subjects. Acta Pharmacol Sin, 2003, 24 (12): 1277-1280
62. Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, Kunert-Keil C. CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther, 2004, 75(3): 213-222
63. Grozinger M, Dragicevic A, Hiemke C, Shams M, Muller MJ, Hartter S. Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine. Pharmacopsychiatry, 2003, 36(1):3-6
64. Brosen K. Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie, 2004, 59(1): 5-12
65. Eap CB, Bondolfi G, Zullino D, Savary-Cosendai L, Powell-Golay K, Kosel M, et al. Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers. J Clin Psychopharmacol, 2001,21(3): 330-334
66. Alfaro CL, Lam YW, Simpson J. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol, 2000, 40 (1): 58-66
67. Yoon YR, Cha IJ, Shon JH, Kim KA, Cha YN, Jang IJ, et al. Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects. Clin Pharmacol Ther, 2000, 67(5):567-576
68. Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, et al. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol, 2003,59: 385-388
69. Lin LY, Di Stefano EW, Schmitz DA, Hsu L, Ellis SW, Lennard MS, Tucker GT, Cho AK. Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Drug Metab Dispos. 1997, 25(9):1059-1064
70. Masimirembwa C, Hasler J, Bertilssons L, Johansson I, Ekberg O, Ingelman-Sundberg M. Phenotype and genotype analysis of debrisoquine hydroxylase (CYP2D6) in a black Zimbabwean population. Reduced enzyme activity and evaluation of metabolic correlation of CYP2D6 probe drugs. Eur J Clin Pharmacol. 1996, 51(2):117-122
71. Huang J, Chuang SK, Cheng CL, Lai ML. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin Pharmacol Ther. 1999, 65(4):402-407
72. Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol, 1993,44(4): 349-355
73. Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, Kunert-Keil C. CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther, 2004, 75(3): 213-222
74. Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity[J]. Clin Pharmacol Ther, 2000, 67: 466-477
75. Etienne LM, Marie YB, Bettina AH. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol, 2001, 21 (2): 175-184
76. B. Mistry, J. Leslie, N.E. Eddington. A sensitive assay of metoprolol and its major metabolite α-hydroxy metoprolol in human plasma and determination of dextromethorphan and its metabolite dextrorphan in urine with high performance liquid chromatography and fluorometric detection. J. Pharm. Biomed. Anal. 1998, 16: 1041-1049
77. 黄蓓琳,吴娟,王洪泉,等. 高效液相色谱法测定人血清中酒石酸美托洛尔浓度. 中国现代应用药学杂志,2000,17(5):408-410
78. Miguel AC, Emilio GQ, Belen S, et al. Simultaneous stereoselective analysis of tramadol and its primary phase I metabolites in plasma by liquid chromatography application to a pharmacokinetic study in humans. J Chromatogr A, 2004, 1031: 219-228
1.孙忠实,朱珠. 药物代谢性相互作用研究进展[J]. 医药世界,2004; 8:60-1
2. 付良青,吴德政. 细胞色素 P4502D6 的研究进展[J]. 中国临床药理学杂志,2000; 16 (6): 453- 7
3. http://www.imm.ki.se/CYPallele/cyp2d6.htm
4. Vandel P, Haffen E, Nezelof S. Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients[J]. Hum Psychopharmacol. 2004; 19 (5): 293- 8
5. Eap CB, Sirot EJ, Baumann P. Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies[J]. Ther Drug Monit, 2004; 26 (2): 152- 5
6. Brosen K. Some aspects of genetic polymorphism in the biotransformation of antidepressants[J]. Therapie, 2004; 59(1): 5-12
7. Eap CB, Bondolfi G, Zullino D, Savary-Cosendai L, Powell-Golay K, Kosel M, et al. Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers[J]. J Clin Psychopharmacol, 2001; 21(3): 330-4
8. Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, et al. Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients[J]. Pharmacol Res, 1995; 31 (6): 347-53
9.Yoon YR, Cha IJ, Shon JH, Kim KA, Cha YN, Jang IJ, et al. Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects[J]. Clin Pharmacol Ther, 2000; 67(5):567-76
10. Kari L, Steven DB, Harry B, Juha R, Jutta H, Harry S, et al. Effect of the novel anxiolytic drug deramciclane on cytochrome P450 2D6 activity as measured by desipramine pharmacokinetics[J]. Eur J Clin Pharmacol, 2004; 59: 893-8
11. Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine[J]. Eur J Clin Pharmacol, 1993; 44(4): 349-55
12. Tsuyoshi F, Isamu Y, Yuko N, Qian Z, Masako O, Kanji T, et al. Effect of CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers[J]. Br J Clin Pharmacol, 1999; 47: 450-3
13. Albers LJ, Reist C, Vu RL. Effect of venlafaxine on imipramine metabolism[J]. Psychiatry Res, 2000; 96(3): 235-43
14. Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, et al. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients[J]. Eur J Clin Pharmacol, 2003; 59: 385-8
15.Chen B, Cai WM. Influence of CYP2D6*10B genotype on pharmacokinetics of propafenone enantiomers in Chinese subjects[J]. Acta Pharmacol Sin, 2003; 24 (12): 1277-80
16. 杨露芳,诸骏仁. 普罗帕酮的药物相互作用[J]. 中华心血管病杂志,1997; 25(6): 480-2
17. Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, Kunert-Keil C, et al. CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects[J]. Clin Pharmacol Ther, 2004; 75(3): 213-22
18. Graff DW, Williamson KM, Pieper JA, Carson SW, Adams KF Jr, Cascio WE, et al. Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients[J]. J Clin Pharmacol, 2001; 41(1): 97-106
19. Grozinger M, Dragicevic A, Hiemke C, Shams M, Muller MJ, Hartter S. Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine[J]. Pharmacopsychiatry, 2003; 36(1):3-6
20. Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, et al. Inhibition of Risperidone Metabolism by Fluoxetine in Patients With Schizophrenia: A Clinically Relevant Pharmacokinetic Drug Interaction[J]. J Clin Psychopharmacol, 2002; 22(4): 419-23
21. Taylor D. Pharmacokinetic interactions involving clozapine[J]. Br J Psychiatry, 1997; 171: 109-12
22.Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6[J]. Clin Pharmacokinet, 1995; 29 Suppl 1:10-8
23. Alfaro CL, Lam YW, Simpson J. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations[J]. J Clin Pharmacol, 2000; 40 (1): 58-66.
24.Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P, et al. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity[J]. Clin Pharmacol Ther, 2000; 67: 466-77
25. Etienne LM, Marie YB, Bettina AH. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans[J]. J Clin Psychopharmacol, 2001; 21 (2): 175-84
26.Eap CB, Lessard E, Baumann P, Brawand-Amey M, Yessine MA, Hara GO, et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans[J]. Pharmacogenetics, 2003; 13 (1): 39-47
27.Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents[J]. Clin Pharmacokinet. 1998; 35(4): 275-91
28. Kelly DV, Beique LC, Bowmer MI. Extrapyramidal symptoms with ritonavir/indinavir plus risperidone[J]. Ann Pharmacother. 2002; 36(5):827-30
29. Jover F, Cuadrado JM, Andreu L, Merino J. Reversible coma caused by risperidone-ritonavir interaction[J]. Clin Neuropharmacol. 2002; 25(5):251-3
30. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection[J]. Drugs, 2003; 63(8):769-802
31.王娜,刘会臣,候艳宁. 细胞色素 P4502D6 与药物代谢[J]. 中国临床药理学杂志,2001; 17 (4):308-12
32. Spina E, Avenoso A, Campo GM. Phenobarbital induces the 2-hydroxylation of desipramine[J]. Ther Drug Monit, 1996; 18(1): 60- 4
