Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor

British Journal of Pharmacology

Volumn 165, Issue 5, 2012, Pages 1595-1608

  Hoffart, E ^a   Ghebreghiorghis, L ^b   Nussler, A K ^a,c   Thasler, W E ^d   Weiss, T S ^e   Schwab, M ^a,f   Burk, O ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

^b UNIVERSITY OF STUTTGART   (Germany)

^c CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^d LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^e UNIVERSITY OF REGENSBURG   (Germany)

^f UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

Author keywords

atorvastatin; CAR; drug interaction; induction; metabolites; para hydroxy atorvastatin; PXR

Indexed keywords

ANDROSTANE RECEPTOR; ATORVASTATIN; CYTOCHROME P450; DRUG METABOLITE; MESSENGER RNA; PREGNANE X RECEPTOR; STEROID RECEPTOR; UNCLASSIFIED DRUG;

ARTICLE; CAR GENE; CONTROLLED STUDY; CYP3A4 GENE; GENE; GENE ACTIVATION; GENE EXPRESSION REGULATION; GENE INTERACTION; GENE TARGETING; HUMAN; HUMAN CELL; LIGAND BINDING; LIVER CELL; MARKER GENE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PXR GENE; REPORTER GENE; SURFACE PLASMON RESONANCE; TRANSPOSON; TWO HYBRID SYSTEM;

ARYL HYDROCARBON HYDROXYLASES; CELL LINE, TUMOR; CO-REPRESSOR PROTEINS; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; GENES, REPORTER; HEP G2 CELLS; HEPATOCYTES; HEPTANOIC ACIDS; HUMANS; LIGANDS; MEMBRANE TRANSPORT PROTEINS; OXIDOREDUCTASES, N-DEMETHYLATING; PROMOTER REGIONS, GENETIC; PYRROLES; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, STEROID; RNA, MESSENGER;

EID: 84857089774     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01665.x     Document Type: Article

References (49)

1. Alexander SPH, Mathie A, Peters JA, (2011). Guide to Receptors and Channels (GRAC), 5th edn. Br J Pharmacol 164 (Suppl. 1): S1-S324.
2. Arnold KA, Eichelbaum M, Burk O, (2004). Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor. Nucl Recept 2: 1.
3. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, (1998). Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Artherosclerosis 138: 271-280.
4. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ, (2005). Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 78: 154-167.
5. Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, et al,. (2002). Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277: 24280-24288.
6. Burk O, Arnold KA, Nussler AK, Schaeffeler E., Efimova E, Avery BA, et al,. (2005). Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67: 1954-1965.
7. Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, et al,. (2005). Differential interaction of 3 hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33: 537-546.
8. Dring AM, Anderson LE, Qamar S, Stoner MA, (2010). Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. Chem Biol Interact 188: 512-525.
9. Feidt D, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, et al,. (2010). Profiling induction of cytochrome P450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab Dispos 38: 1589-1597.
10. Geick A, Eichelbaum M, Burk O, (2001). Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276: 14581-14587.
11. Hochman JH, Pudvah N, Qiu J, Yamazaki M, Tang C, Lin JH, et al,. (2004). Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm Res 21: 1686-1691.
12. Horton JD, Goldstein JL, Brown MS, (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109: 1125-1131.
13. Howe K, Sanat F, Thumser AE, Coleman T, Plant N, (2011). The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica 41: 519-529.
14. Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, et al,. (2001). Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 29: 1454-1459.
15. Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, et al,. (2000). Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 28: 1369-1378.
16. Jinno H, Tanaka-Kagawa T, Hanioka N, Ishida S, Saeki M, Soyama A, et al,. (2004). Identification of novel alternative splice variants of human constitutive androstane receptor and characterization of their expression in the liver. Mol Pharmacol 65: 496-502.
17. Kahri J, Valkonen M, Bäcklund T, Vuoristo M, Kivistö KT, (2005). Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol 60: 905-907.
18. Kameyama Y, Yamashita K, Kobayashi K, Hosakawa M, Chiba K, (2005). Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1 5, SLCO1B1 15 and SLCO1B1 15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics 15: 513-522.
19. Kantola T, Kivistö KT, Neuvonen PJ, (1998). Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 64: 58-65.
20. Keskitalo JE, Kurkinen KJ, Neuvoneni, PJ, Niemi M, (2008). ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 84: 457-461.
21. Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M, et al,. (2005). Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos 33: 924-929.
22. Kobayashi K, Saito K, Takagi S, Chiba K, (2010). Ligand-dependent assembly of Pregnane X Receptor, constitutive androstane receptor and liver X receptor is applicable to identify ligands. Drug Metab Lett 4: 88-94.
23. Kocarek TA, Dahn MS, Cai H, Strom SC, Mercer-Haines NA, (2002). Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme A inhibitors in primary cultured human hepatocytes. Drug Metab Dispos 30: 1400-1405.
24. Lau YY, Huang Y, Frassetto L, Benet L, (2007). Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther 81: 194-204.
25. Lee YJ, Lee MG, Lim LA, Jang SB, Chung JY, (2010). Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects. Int J Clin Pharmacol Ther 48: 36-45.
26. Lennernäs H, (2003). Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42: 1141-1160.
27. Li H, Wang H, (2010). Activation of xenobiotic receptors: driving into the nucleus. Expert Opin Drug Metab Toxicol 6: 409-426.
28. Marino M, di Masi A, Trezza V, Pallottini V, Polticelli F, Ascenzi P, (2011). Xenosensors CAR and PXR at work: impact on statin metabolism. Curr Drug Metab 12: 300-311.
29. di Masi A, De Marinis E, Ascenzi P, Marino M., (2009). Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Mol Aspects Med 30: 297-343.
30. Monostory K, Pascussi JM, Szabõ P, Temesvári M, Köhalmy K, Acimovic J, et al,. (2009). Drug interaction potential of 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3-yl)ethanol (LK-935), the novel nonstatin-type cholesterol-lowering agent. Drug Metab Dispos 37: 375-385.
31. Neuvonen PJ, Niemi M, Backman JT, (2006). Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80: 565-581.
32. Nussler AK, Nussler NC, Merk V, Brulport M, Schormann W, Yao P, et al,. (2009). The holy grail of hepatocyte culturing and therapeutic use. In:, Santin M, (ed.). Strategies in Regenerative Medicine. Springer: New York, pp. 283-320.
33. Omiecinski CJ, Coslo DM, Chen T, Laurenzana EM, Peffer RC, (2011). Multi-species analyses of direct activators of the constitutive androstane receptor. Toxicol Sci 123: 550-562.
34. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M, (2007). Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82: 726-733.
35. Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, Black DM, Stein EM, Corella D, et al,. (2001). Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner. Atherosclerosis 158: 183-193.
36. Pissios P, Tzameli I, Kushner P, Moore DD, (2000). Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding. Mol Cell 6: 245-253.
37. Poli A, (2007). Atorvastatin: pharmacological characteristics and lipid-lowering effects. Drugs 67 (Suppl. 1): 3-15.
38. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, et al,. (2002). Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 30: 505-512.
39. Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, et al,. (2005). AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line. J Biol Chem 280: 4367-4373.
40. Riedmaier S, Klein K, Hofmann U, Keskitalo JE, Neuvonen PJ, Schwab M, et al,. (2010). UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther 87: 65-73.
41. Sakaeda T, Fujino H, Komoto C, Kakumoto M, Jin JS, Iwaki K, et al,. (2006). Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharm Res 23: 506-512.
42. Shindo S, Numazawa S, Yoshida T, (2007). A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction. Biochem J 401: 735-741.
43. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, et al,. (2006). Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 114: 2655-2662.
44. Synold TW, Dussault I, Forman BM, (2001). The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7: 584-590.
45. Thasler WE, Weiss TS, Schillhorn K, Stoll PT, Irrgang B, Jauch KW, (2003). Charitable state-controlled foundation Human Tissue and Cell Research: ethic and legal aspects in the supply of surgically removed human tissue for research in the academic and commercial sector in Germany. Cell Tissue Bank 4: 49-56.
46. Weiss TS, Pahernik S, Scheruebl I, Jauch KW, Thasler WE, (2003). Cellular damage to human hepatocytes through repeated application of 5-aminolevulinic acid. J Hepatol 38: 476-482.
47. Willrich MA, Hirata MH, Hirata RD, (2009). Statin regulation of CYP3A4 and CYP3A5 expression. Pharmacogenomics 10: 1017-1024.
48. Wu X, Whitfield LR, Stewart BH, (2000). Atorvastatin transport in the Caco-2 cell model: contribution of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res 17: 209-215.
49. Yamasaki D, Nakamura T, Okamura N, Kokudai M, Inui N, Takeuchi K, et al,. (2009). Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur J Pharm Sci 37: 126-132.