Die Bedeutung genetischer Polymorphismen im Enzym Cytochrom P450 2C9 für Pharmakokinetik und Wirkungen der Nichtsteroidalen Antiphlogistika Diclofenac und IbuprofenGeorg Freytag11.11.1.111.1.221.23605#3601.31.3.14604#2351.3.25605#991.41.4.161.4.21.4.2.171.4.2.21.4.31.4.3.181.4.3.21.4.49604#135603#434101.4.51112131.51.6141522.12.1.1152.1.216604#2112.1.317603#1932.1.42.1.5182.1.62.1.72.1.8192.1.92.1.102.1.11202.1.122.1.132.2212.2.1603#2592.2.222599#3542.2.3603#359232.2.42.2.524603#286605#179604#12425604#467603#3692.32.3.12.3.1.1262.3.1.2272.3.1.3282.3.2584#290590#5472.3.2.1292.3.2.22.3.2.3302.3.3584#22831590#5782.3.3.12.3.3.2322.3.3.32.3.42.3.4.1332.3.4.22.3.4.3342.42.4.135603#3662.4.22.4.32.53633637595#4253.13.1.1603#5183.1.1.138894#5403.1.1.2393.1.2605#52540971#5783.23.2.1604#559413.2.1.13.2.1.23.2.1.3423.2.1.4901#5293.2.243604#59144899#59344.14.1.1454.1.1.14.1.1.246474.1.24.1.2.1484.1.2.24.24.2.1494.2.1.14.2.2504.2.351AbkürzungenLiteraturverzeichnisErklärung an Eides Statt Publikationsliste Zur PersondeInhaltsverzeichnisHilfe Literaturverzeichnis Abramson SR, Weissmann G. The mechanisms of action on nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1989: 32 1-9. Adams SS, Bresloff P, Mason CG. Pharmacological differences between the optical isomers of ibuprofen: Evidence for the metabolic inversion of the (-) isomer.J Pharm Pharmacol1976: 28 256-257. Aithal GP, Day CP, Leathart JB, Daly AK. Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. Pharmacogenetics 2000 : 10(6) 511-518. Avgerinos A, Hutt AJ. Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers. Chirality 1990: 2 249-256. Aynacioglu AS, Brockmöller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, Nacak M, Roots I. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol1999: 48(3), 409-415. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000: 102, 840-845. Bertz RJ und Grannemann GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmakokinetic interactions. Clin Pharmacokinet 1997: 32 210-258 Bhasker CR, Miners JO, Coulter S, Birkett DJ. Allelic and functional variability of cytochrome P4502C9.Pharmacogenetics 1997: 7 51-58. Bird ED und Schwalbe jr. FC. Prolonged hypoglycemia secondary to tolbutamide. Ann Intern Med1965: 62 110-112. Boelsterli UA, Zimmermann HJ, Kretz-Rommel. Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 1995: 25 207-235. Bolten WW, Lang B, Wagner AV, Krobot KJ. Konsequenzen und Kosten der NSA-Gastropathie in Deutschland.Akt Reumatol 1999: 24, 127-134. Bonnabry P, Leemann T, Dayer P. Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam. Eur J Clin Pharmacol 1996: 49(4) 305-308. Bort R, Mace K, Boobis A, Gomez-Lechon MJ, Pfeifer A, Castell J. Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol 1999: 58(5), 787-796. Brockmöller J, Kirchheiner J, Meisel C, Roots I. Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenomics2000: 1(2) 125-151. Cairns J, Overbaugh J, Miller S. The origin of mutants. Nature 1988: 335 142-145. Chesne C, Guyomard C, Guillouzo A, Schmid J, Ludwig E, Sauter T. Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica 1998: 28(1), 1-13. Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH :cytochrome P450 oxidoreductase. Pharmacogenetics 1997: 7(3), 203-210. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998: 104(5), 413-421. Davies NM. Clinical pharmacokinetics of ibuprofen: the first 30 years. Clin Pharmacokinet 1998: 34 101-154. Day RO, Williams K, Graham GG, Lee EJ, Knihinicki RD, Champion GD. Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 1988: 43 480-487. De Morais SMF, Schweikl H, Blaisdell J, Goldstein JA. Gene structure and upstream regulatory regions of human CYP 2C9 and CYP 2C18. Biochem Biophys Res Commun 1993: 194, 194-201. De Waziers I, Cugnenc PH, Leroux J-P, Beaune PH. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther1990: 253 387-393. Dorado R, Norberto MJ, Berecz R, Martinez M, De la Rubia M, Yasar Ü. Cyp2C9 genotype and diclofenac hydroxylation in a Spanish population. Pharmacology and toxicology 2001: 89 102. Evans AM , Nation RL, Sansom LN, Bochner F, Somogyi AA. Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S( +)-ibuprofen. Br J Clin Pharmacol 1991: 31 131-138. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001: 345 433-442. Forth W, Henschler D, Rummel W Starke K. Allgemeine und spezielle Pharmakologie und Toxikologie. Spektrum Akademischer Verlag,

Heidelberg, Berlin, Oxford

1996. Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991: 5(9), 2304-2312. Garrod AE. Inborn errors of metabolism. University Press,

New York Oxford

: 1909 Goldstein, JA, de Morais SMF. Biochemistry and molecular biology of the human CYP 2C subfamily. Pharmacogenetics 1994: 4 285-299. Gotoh O. Substrate recognition sites in cytochrome P-450 family 2 (CYP 2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 1992: 267 83-90. Gray IC, Nobile C, Muruseu R, Ford S, Spurr NK. A 2 ,4 megabase physical map spanning the Cyp2C gene cluster on chromosome 10q24.Genomics 1995: 28 328-332. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996: 333(2), 447-458. Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 2003: 73(1), 122-130. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA1975: 72(8), 2994-2998. Hamman MA, Thompson GA, Hall SD. Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 1997: 54(1), 33-41. He M, Korzekwa KR, Jones JP, Rettie AE, Trager WF. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys1999: 372(1), 16-28. Hempel SL, Monick MM, Hunninghake GW. Lipopolysaccharide induces prostaglandin H synthase-2 protein and mRNA in human alveolar macrophages and blood monocytes. J Clin Invest 1994: 93(1 ), 391-396. Hutzler JM, Hauer MJ, Tracy TS. Dapsone activation of CYP2C9-mediated metabolism: evidence for activation of multiple substrates and a two-site model. Drug Metab Dispos 2001: 29(7), 1029-1034. Iber FL. Drug metabolism in heavy consumers of ethyl alcohol. Clin Pharmacol Ther 1977: 22, 735-742. Ingelmann-Sundberg M, Oscarson M, Mc Lellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends in Pharmacological Sciences 1999: 20 342-349. Inoue K, Yamazaki H, Imiya K, Akasaka S, Guengerich FP, Shimada T. Relationship between CYP 2C9 and 2C19 genotypes and tolbutamide methylhydroxylation and S-mephenytoin 4’-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997: 7 103-113. Jones BC, Hawksworth G, Horne VA, Newlands A, Morsman J, Tute MS, Smith DA. Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Drug Metab Dispos 1996:24 (2), 260-266. Jones JP, He M, Trager WF, Rettie AE. Three dimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9.Drug Metab Dispos 1996: 24 1-6. Kaiser DG, VanGiessen GJ, Reisecher RJ, Wechter WJ. Isomeric inversion of ibuprofen (R)-entiomers in humansJ Pharm Sci 1976:65 269-273. Kater RMH, Roggin G, Tobon F, Zieve P, Iber FL. Increased rate of clearance of drugs from the circulation of alcoholics. Am J Med Sci 1969: 258 35-39. Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 1999: 9(1), 71-80. Kirchheiner J, Stormer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 2003: 13(8), 473-480. Kreeger N. Tolbutamide-induced hypoglycemia. N Engl J Med 1962: 266 818-820. Kutt H, Wolk M, MC Dowell F. Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology1964: 14 542-548 Lee EJD, Williams K, Day R, Graham G, Champion D. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985: 19 669-674. Leemann T, Transom C, Dayer P. Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4’-hydroxylation in human liverLife Sci 1993: 52 29-34. Löffler G. Basiswissen Biochemie mit Pathobiochemie. Springer Verlag.

Berlin. Heidelberg. New York. Barcelona.

Hongkong.

London.

Mailand.

Paris.

Singapur.

Tokio

. 2001. Lötsch J, Muth-Selbach U, Tegeder I, Brune K, Geisslinger G. Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate. Br J Clin Pharmacol 2001: 52(4), 387-398. Macia MA, Frias J, Carcas AJ, Guerra P, Valiente R, Lucero ML. Comparative bioavailability of a dispersible formulation of diclofenac and f inding of double plasma peaks. Int J Clin Pharmacol Ther1995: 33(6), 333-339. Maier R, Menasse R, Riesterer L, Pericin C, Ruegg M, Ziel R. The pharmacology of diclofenac sodium (Voltarol). Rheumatol Rehabil. 1979: Suppl 2, 11-21. Mancy A, Antignac M, Minoletti C, Dijols S, Mouries V, Duong NT, Battioni P, Dansette PM, Mansuy D. Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry1999: 38(43), 14264-14270. Mancy A, Broto P, Dijols S, Dansette PM, Mansuy D. The substrate binding site of human liver cytochrome P4502C9: an approach using designed tienilic acid derivates and molecular modeling. Biochemistry 1995: 34 10365-10375. Meehan RR, Gosden JR, Rout D, Hastle ND, Friedberg T, Adesnik M, Buckland R, van Heyningen V, Fletcher J, Spurr NK, Sweeney J, Wolf CR. Human cytochrome P-450 PB-1: A multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Genet 1988: 42 26-37. Menasse R, Hedwall PR, Kraetz J, Pericin C, Riesterer L, Sallmann A, Ziel R, Jaques R. Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol Suppl 1978: 22, 5-16. Meyer UA. The molecular basis of genetic polymorphism of drug metabolism of drug metabolism. J Pharm 1994: 46 409-415. Mills RFN, Adams SS, Clife EE, Dickinson W, Nicholson JS. The metabolism of ibuprofen. Xenobiotica 1973 : 3 589-598. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998: 45(6), 525-538. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci 1993: 90(24), 11693-11697. Morin S, Loriot MA, Poirier JM, Tenneze L, Beaune PH, Funck-Brentano C, Jaillon P, Becquemont L. Is diclofenac a valuable CYP2C9 probe in humans? Eur J Clin Pharmacol 2001: 56(11), 793-797. Motulsky AG. Drug reactions, enzymes and biochemical genetics. JAMA1957: 165 835-837. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001: 286(8), 954-959. Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab Dispos 1998: 26(3), 261-266. Nebert DW, Adesnick M, Coon MJ, Estabrook RW, Gonzales FJ, Guengerich FP, Gunsalus IC, Johnson EF, Kemper B, Levin W, Phillips IR, Sato R, Waterman M. The P450 gene superfamily: recommended nomenclature. DNA 1987: 6 1-11 Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997: 60, 265-271. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus JC, Nebert DW. P 450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996: 6, 1-42. Odani A, Hashimoto Y, Otsuki Y, Uwai Y, Hattori H, Furusho K, Inui K. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther

1997

: 62(3), 287-292. O'Sullivan MG, Huggins EM Jr, Meade EA, DeWitt DL, McCall CE. Lipopolysaccharide induces prostaglandin H synthase-2 in alveolar macrophages.Biochem Biophys Res Commun1992: 187(2), 1123-7. Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, Cipollone F, Ganci A, Creminon C, Maclouf J . Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994: 271(3), 1705-12. Patrono C, Ciabattoni G, Pugliese F, Pinca E, Castrucci G, De Salvo A, Cattani P. Radioimmunoassay measurement of stable metabolites of pla telet arachidonic acid: a convenient method for the in vitro and ex vivo evaluation of cyclo-oxygenase inhibitors. Agents Actions Suppl 1980a: 7, 256-259. Patrono C, Ciabattoni G, Pugliese F, Pinca E, Castrucci G, De Salvo A, Satta MA, Parachini M. Radioimmunoassay of serum thromboxane B2: a s imple method of assessing pharmacologic effects on platelet functionAdv Prostaglandin Thromboxane Res1980b : 6, 187-191. Patrono C, Patrignani P, Garcia Rodriguez LA. Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest 2001: 108(1), 7-13. Relling MV, Aoyama T, Gonzales FJ, Meyer UA. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Ther 1990: 252 442-447. Rodrigues AD, Kukulka MJ, Roberts EM, Ouellet D, Rodgers TR. (O-methyl 14C )naproxen O-demethylase activity in human liver microsomes: evidence for the involvement of cytochrome P4501A2 and P4502C9/10. Drug Metab Dispos1996: 24(1) , 126 -136. Rudy AC, Knight PM, Brater DC, Hall SD. Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment. J Pharmacol Exp Ther 1995 : 273, 88-93. Rudy AC, Knight PM, Brater DC, Hall SD. Stereoselective metabolism of ibuprofen in humans. Administration of R-, S- and racemic ibuprofen. J Pharmacol Exp Ther 1991: 259, 1133-1139. Sandor P, Sellers EM, Dumbrell M, Khouw V. Effect of short-and long-term alcohol use on phenytoin kinetics in chronic alcoholics. Clin Pharmacol Ther 1981: 30 390-397. Scott J, Poffenbarger PL. Pharmacogenetics of tolbtamide metabolism in humans. Diabetes 1979: 28 (1), 41-51 Schmedtje JF, Ji YS, Liu WL, DuBois RN, Runge MS. Hypoxia induces cyclooxygenase-2 via the NF-kappaB p65 transcription factor in human vascular endothelial cells. J Biol Chem 1997: 272 601-608. Schmidt G. Antirheumatika und Antiphlogistika. In: Schwabe U, Paffrath D (Hrsg.): Arzneiverordnungsreport 2000. Springer-Verlag

Berlin, Heidelberg, New York

2001. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol2001: 52(4), 447-450 Seppälä E, Laitinen O, Vapaatalo H. Comparative study on the effects of acetylsalicylic acid, indomethacin and paracetamol on metabolites o f arachidonic acid in plasma, serum and urine in man. Int J Clin Pharmacol Res 1983: 3(4), 265-269. Shen S, Marchick MR, Davis MR, Doss GA, Pohl LR. Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac.Chem Res Toxicol 1999: 12(2), 214-222. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994: 270 (1), 414-423. Shimamoto J, Ieiri I, Urae A, Kimura M, Irie S, Kubota T, Chiba K, Ishizaki T, Otsubo K, Higuchi S. Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele. Eur J Clin Pharmacol. 2000: 56(1 ), 65-68. Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF, Rettie AE. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997: 7, 361-367. Stierlin H, Faigle JW. Biotransformation of diclofenac sodium (Voltaren) in animals and in man. II. Quantitative determination of the unchanged drug and principal phenolic metabolites, in urine and bile. Xenobiotica 1979: 9(10), 611-21. Stryer L. Biochemie. Spektrum Akademischer Verlag,

Heidelberg, Berlin, Oxford

1996. Stubbbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P4502C9 locus.Pharmacogenetics 1996: 6, 429-439. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA. The role of the Cyp2C9- Leu( 359) allelic variant in the tolbutamide polymorphism. Pharmacogenetics1996: 6, 341-349. Takahashi H, Kashima T, Nomoto S, Iwade K, Tainaka H, Shimizu T, Nomizo Y, Muramoto N, Kimura S, Echizen H. Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes Pharmacogenetics 1998: 8, 365-373. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K. CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics2000: 10(2), 95-104. Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD. Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. J Pharmacol Exp Ther 2000: 293(2), 453-459. Tang C, Shou M, Rodrigues AD. Substrate-dependent effect of acetonitrile on human liver microsomal cytochrome P450 2C9 (CYP2C9) activity.Drug Metab Dispos 2000: 28(5), 567-572. Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, Rose MJ, Gelmann A, Greenberg HE, De Lepeleire I, Van Hecken A, De Schepper PJ, Ebel DL, Schwartz JI, Rodrigues AD. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.Pharmacogenetics 2001: 11(3), 223-235. Tang W, Stearns RA, Bandiera SM, Zhang Y, Raab C, Braun MP, Dean DC, Pang J, Leung KH, Doss GA, Strauss JR, Kwei GY, Rushmore TH, Chiu SH, Baillie TA. Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites.Drug Metab Dispos 1999a: 27(3), 365-372. Tang W, Stearns RA, Wang RW, Chiu SH, Baillie TA. Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem Res Toxicol 1999b: 12(2), 192-199. Todd PA, Sorkin EM. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1988: 35(3), 244-285. Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR. Studies of flurbiprofen 4'-hydroxylation. Additional evidence suggesting the sole involvement of cytochrome P450 2C9. Biochem Pharmacol 1996: 52(8), 1305-1309. Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR. Involvement of multiple cytochrome P450 isoforms in naproxen O-demethylation. Eur J Clin Pharmacol1997: 52(4), 293-298. Tracy TS, Rosenbluth BW, Wrighton SA, Gonzalez FJ, Korzekwa KR. Role of cytochrome P450 2C9 and an allelic variant in the 4'-hydroxylation of (R )- and (S)-flurbiprofen. Biochem Pharmacol 1995: 49(9), 1269-1275. Vacas MI, Del Zar MM, Martinuzzo M, Falcon C, Carreras LO, Cardinali DP. Inhibition of human platelet aggregation and thromboxane B2 production by melatonin. Correlation with plasma melatonin levels. J Pineal Res 1991: 11(3-4), 135-139. Vane J. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature-New Biol 1971 : 231, 232-235. Vane J. Towards a better aspirinNature 1994 : 367, 215-216. Vane JR, Botting RM. A better understanding of anti-inflammatory drugs based on isoforms of cyclooxygenase (COX-1 and COX-2). Adv Prostaglandin Thromboxane Leukot Res 1995: 23, 41-48. Veronese ME, Doecke CJ, Mackenzie PI, McManus ME, Miners JO, Rees DL, Gasser R, Meyer UA, Birkett DJ. Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily.Biochem J 1993: 289(2), 533-538. Vial JH, McLeod LJ, Roberts MS. Rebound elevation in urinary thromboxane B2 and 6-keto-PGF1 alpha excretion after aspirin withdrawal. Adv Prostaglandin Thromboxane Leukot Res1991 : 21A, 157-160. Wallace JL, Bak A, McKnight W, Asfaha S, Sharkey KA, MacNaughton WK. Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity.Gastroenterology 1998:115(1), 101-109. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A1999: 96 (13), 7563-7568. Wolf CR und Smith G. Pharmacogenetics. Br Med Bull 1999; 55(2), 66-386 Wrigthon SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992: 22, 1-21. Yamazaki H, Inoue K, Chiba K, Ozawa N, Kawai T, Suzuki Y, Goldstein JA, Guengerich FP, Shimada T. Comparative studies on the catalytic roles of cytochrome P450 2C9 and its Cys- and Leu-variants in the oxidation of warfarin, flurbiprofen, and diclofenac by human liver microsomes.Biochem Pharmacol 1998: 56(2), 243-251. Yasar U, Eliasson E, Forslund-Bergengren C, Tybring G, Gadd M, Sjoqvist F, Dahl ML. The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol. 2001: 57(10), 729-735. Webseiten http://drnelson.utmem.edu/CytochromeP450.html; UT Memphis, Department Of Biochemistry 1993: Cytochrome P450 homepage. http://www.imm.ki.se/CYPalleles/default.htm; Karolinska Institutet National Institute Of Environmental Medicine 1999: Human cytochrome P450 (CYP) allele nomenclature committee. http://medicine.iupui.edu/flockhart/; UT Indiana, Department Of Medicine 2002: Cytochrome P450 drug int