İlaç metabolizmasında rol oynayan enzimlerin aktivitelerinin belirlenmesinde in vivo prob ilaç kullanımı

Amaç: Bu derlemede, ilaç metabolizmasında rol oynayan enzimlerin aktivitelerinin belirlenmesinde in vivo prob ilaçların kullanımları hakkında bilgi verilmiştir. Ana bulgular: İlaç metabolizmasında görevli enzimler çeşitli ksenobiyotiklerin biyotransformasyonunda da önemli rol oynar. Dokularda enzim sentezindeki farklılıklara bağlı olarak çoğu ilacın farmakokinetik ve farmakodinamiğinde ve toksik maddelere duyarlılıkta bireylerarası ve etnik farklılıklar gösterilmiştir. Enzim aktivitelerinin belirlenmesinde kullanılan birçok metot vardır. Bunlar, enzim düzeylerinin ölçülmesi (direkt) ve in vivo prob ilaç kullanımı (indirekt) ile fenotipin belirlenmesi ve genotipik metotlar olarak ayrılabilir. Genotipik ve direkt metotların bazı sınırlamaları olduğu için enzim aktivitesinin belirlenmesinde sıklıkla prob ilaçlar kullanılır. İn vivo prob ilaç kullanımı farmakokinetik farklılık, bireysel dozaj rejimi, ilaç etkileşimleri, ilaç toksisitesi ve ksenobiyotiklere duyarlılık gibi klinik farmakoloji ve toksikoloji yönünden ve enzimlerin sentezlendiği organların metabolik kapasitelerinin belirlenmesi açısından önemlidir. Sonuç: Prob ilaçlar, klinik farmakoloji ve toksikoloji alanındaki çalışmalarda kullanılabilme potansiyeline sahiptir.

Use of in vivo probe drugs in the determination of activities of drug metabolizing enzymes

Objective: In this review, the knowledge was given about the use of in vivo probe drugs in the determination of drug metabolizing enzyme activities. Main findings: Drug metabolizing enzymes play an important role in the biotransformation of various xenobiotics. Inter-individuals and ethnics variability have been demonstrated in the pharmacokinetics and pharmacodynamics of many drugs and in susceptibility to toxic substances because of variations in the expression of different enzymes in tissues. A wide range of methods for the determination of enzyme activities is available. These can be divided into those concerned with phenotype determination, either by measurement of enzyme levels (direct) or use of in vivo probe drugs (indirect) and genotyping methods. Because of some limitations of genotyping and direct methods, probe drugs are often used in the determination of enzyme activities. Use of in vivo probe drugs is important for evaluations of several aspects of clinical pharmacology and toxicology such as pharmacokinetic variability, individual dosage regimen, drug interactions, drug toxicity and the susceptibility to xenobiotics and for the determination of metabolic capacities of organs expressing enzymes. Conclusion: Probe drugs have the potential use in clinical pharmacology and toxicology studies.

Kaynakça

1. Steimer W, Potter JM. Pharmacogenetic screening and therapeutic drugs. Clinica Chimica Acta 2002;315:137-55.

2. Morley K. Pharmacogenetics and pharmacogenomics. Office of public policy and ethics institute for molecular bioscience; September 2002;6, Australia.

3. Daly AK. Development of analytical technology in pharmacogenetic research. Naunyn Schmiedebergs Arch Pharmacol 2004;369:133-40.

4. Kivisto KT, Kroemer HK. Use of probe drugs as predictors of drug metabolism in humans. J Clin Pharmacol 1997;37:40S-8S.

5. Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 2000;10:187-216.

6. Schmitz G, Aslanidis C, Lackner KJ. Pharmacogenomics: implications for laboratory medicine. Clinica Chimica Acta 2001;308:43-53.

7. Campbell NRC, Dunnette JH, Mwaluko G, van Loon J, Weinshilboum RM. Platelet phenol sulfotransferase and erythrocyte catechol-O-methyltransferase activities: correlation with methyldopa metabolism. Clin Pharmacol Ther 1984;35:55-63.

8. Price RA, Spielman RS, Lucena AL, van Loon JA, Maidak BL, Weinshilboum RM. Genetic polymorphism for human platelet thermostable phenol sulfotransferase (TS PST) activity. Genetics 1989;122:905-14.

9. Hallier E, Langhof T, Dannappel D, Leutbecher M, Schroder K, Goergens HW et al. Polymorphism of glutathione conjugation of methyl bromide, ethylene oxide and dichloromethane in human blood: Influence on the induction of sister chromatid exchanges (SCE) in lymphocytes. Arch Toxicol 1993;67:173-8.

10. Seidegard J, Pero RW. The hereditary transmission of high glutathione transferase-activity towards trans-stilbene oxide in human mononuclear leukocytes. Hum Genet 1985;69:66-8.

11. Raucy JL, Schultz ED, Wester MR, Arora S, Johnston DE, Omdahl JL et al. Human lymhocyte cytochrome P450 2E1: A putative marker for alcohol-mediated changes in hepatic chlorzoxazone activity. Drug Metab Dispos 1985;25:1429-35.

12. Ford LT, Berg JD. Determination of thiopurine S-methyltransferase activity in erythrocytes using 6-thioguanine as substrate and a non-extraction liguid chromatographic technique. J Chromatogr B 2003;798:111-5.

13. Carrillo, JA, Christensen M, Ramos SI, Alm C, Dahl M, Benitez J et al. Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine. Ther Drug Monit 2000;22:409-17.

14. Cholerton S, Idle ME, Vas A. Comparison of a novel thin-layer chromatographic-fluorescence detection method with a spectrofluorometric method for the determination of 7-hydroxycoumarin in human urine. J Chromatogr 1992;575:325-30.

15. Veronese ME, Miners JO, Randles D, Gregov D, Birkett DJ. Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers. Clin Pharmacol Ther 1990;47:403-11.

16. Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA. Mephenytoin hydroxylation deficiency in Caucasians: freguency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984;36:773-80.

17. Kanazawa H, Okada A, Higaki M, Yokota H, Mashige F, Nakahara K. Stereospecific analysis of omeprazole in human plasma as a probe for CYP2C19 phenotype. J Pharm Biomed Anal 2003;30:1817-24.

18. Jacqz-Aigrain E, Menard Y, Popon M, Mathieu H. Dextromethorphan phenotypes determined by high-performance liquid chromatography and fluorescence detection. J Chromatogr 1989;27:361-3.

19. Marchand LL, Wilkinson GR, Wilkens LR. Genetic and dietary predictors of CYP2E1 activity: A phenotyping study in Hawaii Japanese using chlorzoxazone. Cancer Epidemiol Biomarkers Prev 1999;8:495-500.

20. Totsuka S, Watanabe T, Koyanagi F, Tanaka K, Yasuda M, Manabe S. Increase in urinary excretion of 6b-hydroxycortisol in common marmosets as a marker of hepatic CYP3A induction. Arch Toxicol 1999;73:203-7.

21. Watkins PB, Hamilton TA, Annesley TM, Ellis NC, Kolars JC, Voorhees JJ. The erythromycin breath test as a predictor of cyclosporine blood levels. Clin Pharmacol Ther 1990;48:120-9.

22. Rajaa AM, Ericsson Ö, Tybring G, Gustafsson LL, Bertilsson L. Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. Eur J Clin Pharmacol 2003;59:23-8.

23. Alwaiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. Trimethylaminuria-the detection of carriers using a trimethylamine load test. J Inherit Metab Dis 1989;12:80-5.

24. Grant DM, Tang BK, Kalow W. Polymorphic N-acetylation of a caffeine metabolite. Clin Pharmacol Ther 1983;33:355-9.

25. Akgür SA, Öztürk P, Solak I, Moral AR, Ege B. Human serum paraoxonase (PON1) activity in acute organophosphorous insecticide poisoning. Forensic Sci Int 2003;133:136-40.

26. Chainuvati S, Nafziger AN, Steven LJ, Gaedigk A, Kearns GL, Sellers E, et al. Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the “Cooperstown 5+1 cocktail”. Clin Pharmacol Ther 2003;74: 437-47.

27. Johnson JA, Herring VL, Wolfe MS, Relling MV. CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. JPET 2000;294:1099-105.

28. Zaigler M, Tantcheva-Poor I, Fuhr U. Problems and perspectives of phenotyping for drug-metabolizing enzymes in man. Int J Clin Pharmacol Ther 2000;37:1-9.

29. Fuhr U, Rost KL, Engelhardt R, Sachs M, Liermann D, Belloc C et al. Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations. Pharmacogenetics 1996;6:159-76.

30. Rostami-Hodjegan A, Nurminen S, Jackson PR, Tucker GT. Caffeine urinary metabolite ratios as markers of enzyme activity: A theoretical assessment. Pharmacogenetics 1996;6:121-49.

31. Tanaka E, Kurata N, Yasuhara H. How useful is the ‘cocktail approach’ for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther 2003;28:157-65.

32. Zhou H, Tong Z, James FM. “Cocktail” approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol 2004;44:120-34.

33. Frye RF, Matzke GR, Adedoyin A, Proter JA, Branch RA. Validation of the five-drug “Pittsburgh cocktail” approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther 1997; 62:365-76.

34. Zhu B, Ou-Yang D, Chen X, Huang S, Tan Z, He N, et al. Assessment of cytochrome P450 activity by a five-drug cocktail approach. Clin Pharmacol Ther 2001;70:455-61.

35. Christensen M, Andersson K, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 2003;73:517-28.

36. Schmider J, Brockmoller J, Arold G, Bauer S, Roots I. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 1999;9:725-34.

37. Jackson PR, Tucker GT. Pharmacokinetic-pharmacogenetic modelling in the detection of polymorphisms in xenobiotic metabolism. Ann Occup Hyg 1990;34:653-62.

38. Tanaka E, Breimer DD. In vivo function tests of hepatic drug-oxidizing capacity in patients with liver disease. J Clin Pharm Ther 1997;22:237-49.

39. Tanaka E. Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease. J Clin Pharm Ther 1998;23:161-70.

Kaynak Göster

Genel Tıp Dergisi
  • ISSN: 2602-3741
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1997

14.1b9.7b

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