UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo

Clinical Pharmacology and Therapeutics

Volumn 87, Issue 1, 2010, Pages 65-73

  Riedmaier, S ^a,b   Klein, K ^a,b   Hofmann, U ^a,b   Keskitalo, J E ^c   Neuvonen, P J ^c   Schwab, M ^a,b   Niemi, M ^c   Zanger, U M ^a,b  

^a DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

^c UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; DRUG METABOLITE; GLUCURONOSYLTRANSFERASE 1A1; GLUCURONOSYLTRANSFERASE 1A3; LACTONE;

ALLELE; AREA UNDER THE CURVE; ARTICLE; DRUG BLOOD LEVEL; DRUG HALF LIFE; ENZYME DEGRADATION; GENE FREQUENCY; GENE LINKAGE DISEQUILIBRIUM; GENE LOCUS; GENETIC ASSOCIATION; GENOTYPE PHENOTYPE CORRELATION; HAPLOTYPE; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; HUMAN EXPERIMENT; HUMAN TISSUE; LACTONIZATION; LIVER MICROSOME; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SINGLE DRUG DOSE; SINGLE NUCLEOTIDE POLYMORPHISM; TIME TO MAXIMUM PLASMA CONCENTRATION;

GLUCURONOSYLTRANSFERASE; HEPTANOIC ACIDS; HUMANS; LACTONES; MICROSOMES, LIVER; POLYMORPHISM, GENETIC; PYRROLES;

EID: 72849145686     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2009.181     Document Type: Article

References (45)

1. Law, M. & Rudnicka, A.R. Statin safety: a systematic review. Am. J. Cardiol. 97, 52C-60C (2006).
2. Neuvonen, P.J., Niemi, M. & Backman, J.T. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin. Pharmacol. Ther. 80, 565-581 (2006).
3. Shitara, Y. & Sugiyama, Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-Coa) reductase inhibitors: drug-drug interactions and interindividual diferences in transporter and metabolic enzyme functions. Pharmacol. Ther. 112, 71-105 (2006).
4. Hobbs, F.D. & Southworth, H. achievement of English National Service Framework lipid-lowering goals: pooled data from recent comparative treatment trials of statins at starting doses. Int. J. Clin. Pract. 59, 1171-1177 (2005).
5. Rodrigues, A.C., Hirata, M.H. & Hirata, R.D. The genetic determinants of atorvastatin response. Curr. Opin. Mol. Ther. 9, 545-553 (2007).
6. Mangravite, L.M., Wilke, R.A., Zhang, J. & Krauss, R.M. Pharmacogenomics of statin response. Curr. Opin. Mol. Ther. 10, 555-561 (2008).
7. Link, E. et al. SLCO1B1 variants and statin-induced myopathy-a genomewide study. N. Engl. J. Med. 359, 789-799 (2008).
8. Keskitalo, J.E., Kurkinen, K.J., Neuvoneni, P.J. & Niemi, M. aBCB1 haplotypes diferentially afect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin. Pharmacol. Ther. 84, 457-461 (2008).
9. Pasanen, M.K., Neuvonen, M., Neuvonen, P.J. & Niemi, M. SLCO1B1 polymorphism markedly afects the pharmacokinetics of simvastatin acid. Pharmacogenet. Genomics 16, 873-879 (2006).
10. Hermann, M. et al. Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy. Clin. Pharmacol. Ther. 79, 532-539 (2006).
11. Skottheim, I.B., Gedde-Dahl, A., Hejazifar, S., Hoel, K. & asberg, A. Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Eur. J. Pharm. Sci. 33, 317-325 (2008).
12. Fujino, H., Saito, T., Tsunenari, Y., Kojima, J. & Sakaeda, T. Metabolic properties of the acid and lactone forms of HMG-Coa reductase inhibitors. Xenobiotica 34, 961-971 (2004).
13. jacobsen, W. et al. Lactonization is the critical frst step in the disposition of the 3-hydroxy-3-methylglutaryl-Coa reductase inhibitor atorvastatin. Drug Metab. Dispos. 28, 1369-1378 (2000).
14. Kearney, A.S., Crawford, L.F., Mehta, S.C. & Radebaugh, G.W. The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-Coa reductase inhibitor, CI-981. Pharm. Res. 10, 1461-1465 (1993).
15. Prueksaritanont, T. et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab. Dispos. 30, 505-512 (2002).
16. Li, C., Subramanian, R., Yu, S. & Prueksaritanont, T. acyl-coenzyme a formation of simvastatin in mouse liver preparations. Drug Metab. Dispos. 34, 102-110 (2006).
17. Vickers, S. et al. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG Coa reductase. Drug Metab. Dispos. 18, 476-483 (1990).
18. Billecke, S. et al. Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab. Dispos. 28, 1335-1342 (2000).
19. Goosen, T.C. et al. atorvastatin glucuronidation is minimally and nonselectively inhibited by the fbrates gemfbrozil, fenofbrate, and fenofbric acid. Drug Metab. Dispos. 35, 1315-1324 (2007).
20. Mackenzie, P.I. et al. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet. Genomics 15, 677-685 (2005).
21. Bock, K.W. & Köhle, C. Coordinate regulation of drug metabolism by xenobiotic nuclear receptors: UGTs acting together with CyPs and glucuronide transporters. Drug Metab. Rev. 36, 595-615 (2004).
22. Monaghan, G., Ryan, M., Seddon, R., Hume, R. & Burchell, B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 347, 578-581 (1996).
23. O'Dwyer, P.J. & Catalano, R.B. Uridine diphosphate glucuronosyltransferase (UGT) 1a1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J. Clin. Oncol. 24, 4534-4538 (2006).
24. Barbier, O., Girard, C., Breton, R., Bélanger, A. & Hum, D.W. N-glycosylation and residue 96 are involved in the functional properties of UDP-glucuronosyltransferase enzymes. Biochemistry 39, 11540-11552 (2000).
25. Peterkin, V.C. et al. Limited infuence of UGT1a1&z.ast;28 and no efect of UGT2B7&z.ast;2 polymorphisms on UGT1a1 or UGT2B7 activities and protein expression in human liver microsomes. Br. J. Clin. Pharmacol. 64, 458-468 (2007).
26. Zhang, D. et al. Characterization of the UDP glucuronosyltransferase activity of human liver microsomes genotyped for the UGT1a1&z.ast;28 polymorphism. Drug Metab. Dispos. 35, 2270-2280 (2007).
27. Ménard, V., Girard, H., Harvey, M., Pérusse, L. & Guillemette, C. analysis of inherited genetic variations at the UGT1 locus in the French-Canadian population. Hum. Mutat. 30, 677-687 (2009).
28. Keskitalo, J.E., Zolk, O., Fromm, M.F., Kurkinen, K.J., Neuvonen, P.J. & Niemi, M. aBCG2 polymorphism markedly afects the pharmacokinetics of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther. 86, 197-203 (2009).
29. Iwai, M., Maruo, Y., Ito, M., Yamamoto, K., Sato, H. & Takeuchi, Y. Six novel UDP-glucuronosyltransferase (UGT1a3) polymorphisms with varying activity. J. Hum. Genet. 49, 123-128 (2004).
30. Chen, Y., Chen, S., Li, X., Wang, X. & Zeng, S. Genetic variants of human UGT1a3: functional characterization and frequency distribution in a Chinese Han population. Drug Metab. Dispos. 34, 1462-1467 (2006).
31. Caillier, B. et al. a pharmacogenomics study of the human estrogen glucuronosyltransferase UGT1a3. Pharmacogenet. Genomics 17, 481-495 (2007).
32. Silva, M.A., Swanson, A.C., Gandhi, P.J. & Tataronis, G.R. Statin-related adverse events: a meta-analysis. Clin. Ther. 28, 26-35 (2006).
33. Kobayashi, M. et al. association between risk of myopathy and cholesterol-lowering efect: a comparison of all statins. Life Sci. 82, 969-975 (2008).
34. Barbier, O., Trottier, J., Kaeding, J., Caron, P. & Verreault, M. Lipid-activated transcription factors control bile acid glucuronidation. Mol. Cell. Biochem. 326, 3-8 (2009).
35. Sun, D. et al. Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab. Dispos. 35, 2006-2014 (2007). (Pubitemid 350010805)
36. Kato, Y. et al. Hepatic UDP-glucuronosyltransferases responsible for glucuronidation of thyroxine in humans. Drug Metab. Dispos. 36, 51-55 (2008).
37. Argikar, U.A. & Remmel, R.P. Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica 39, 355-363 (2009).
38. Lang, T. et al. Extensive genetic polymorphism in the human CyP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11, 399-415 (2001).
39. Gomes, A.M. et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics 10, 579-599 (2009).
40. Harraway, J.R. & George, P.M. Use of fully denaturing HPLC for UGT1a1 genotyping in Gilbert syndrome. Clin. Chem. 51, 2183-2185 (2005).
41. Pasanen, M.K., Fredrikson, H., Neuvonen, P.J. & Niemi, M. Diferent efects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther. 82, 726-733 (2007).
42. Strom, T.M. & Wienker, T.F. DeFinetti program. http://ihg2.helmholtz- muenchen.de/cgi-bin/hw/hwa1.pl.
43. Stephens, M. Matthew Stephens Lab. PHaSE.
44. Broad Institute of MIT and Harvard. Haploview. http://www.broad.mit.edu/ mpg/haploview.
45. Bock, K.W. et al. UGT alleles Nomenclature Home Page. UGT Nomenclature Committee (2005). http://www.pharmacogenomics.pha.ulaval.ca/sgc/ugt-alleles/