Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance.

Department of Cell Biology and Genetics Faculty of Science Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic

Zobrazit více v PubMed

Smith SW (2009) Chiral Toxicology: It's the Same Thing … Only Different. Toxicological Sciences 110: 4–30. 10.1093/toxsci/kfp097 PubMed DOI

Bellosta S, Corsini A (2012) Statin drug interactions and related adverse reactions. Expert Opinion on Drug Safety 11: 933–946. 10.1517/14740338.2012.712959 PubMed DOI

Neuvonen PJ, Niemi M, Backman JT (2006) Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80: 565–581. PubMed

Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM (2001) Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrobial Agents and Chemotherapy 45: 3445–3450. PubMed PMC

Prueksaritanont T, Ma B, Tang CY, Meng Y, Assang C, Lu P, et al. (1999) Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. British Journal of Clinical Pharmacology 47: 291–298. PubMed PMC

Scripture CD, Pieper JA (2001) Clinical pharmacokinetics of fluvastatin. Clinical Pharmacokinetics 40: 263–281. PubMed

Olsson AG, McTaggart F, Raza A (2002) Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 20: 303–328. PubMed

Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV (2003) Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clinical Pharmacology & Therapeutics 73: 322–329. PubMed

Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW (2003) Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. British Journal of Clinical Pharmacology 55: 94–99. PubMed PMC

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. European Journal of Pharmaceutical Sciences 37: 126–132. 10.1016/j.ejps.2009.01.009 PubMed DOI

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. 10.3109/00498254.2011.569773 PubMed DOI

Hoffart E, Ghebreghiorghis L, Nussler AK, Thasler WE, Weiss TS, Schwab M, et al. (2012) Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor. British Journal of Pharmacology 165: 1595–1608. 10.1111/j.1476-5381.2011.01665.x PubMed DOI PMC

Plee-Gautier E, Antoun J, Goulitquer S, Le Jossic-Corcos C, Simon B, Amet Y, et al. (2012) Statins increase cytochrome P450 4F3-mediated eicosanoids production in human liver cells: A PXR dependent mechanism. Biochemical Pharmacology 84: 571–579. 10.1016/j.bcp.2012.05.012 PubMed DOI

Kocarek TA, Dahn MS, Cai HB, Strom SC, Mercer-Haines NA (2002) Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme a inhibitors in primary cultured human hepatocytes. Drug Metabolism and Disposition 30: 1400–1405. PubMed

Novotna A, Korhonova M, Bartonkova I, Soshilov AA, Denison MS, Bogdanova K, et al. (2014) Enantiospecific Effects of Ketoconazole on Aryl Hydrocarbon Receptor. Plos One 9. PubMed PMC

Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, et al. (2014) Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells. Plos One 9. PubMed PMC

Rulcova A, Prokopova I, Krausova L, Bitman M, Vrzal R, Dvorak Z, et al. (2010) Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes. J Thromb Haemost 8: 2708–2717. 10.1111/j.1538-7836.2010.04036.x PubMed DOI

Novotna A, Srovnalova A, Svecarova M, Korhonova M, Bartonkova I, Dvorak Z (2014) Differential Effects of Omeprazole and Lansoprazole Enantiomers on Aryl Hydrocarbon Receptor in Human Hepatocytes and Cell Lines. Plos One 9. PubMed PMC

Novotna A, Dvorak Z (2014) Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis. Plos One 9. PubMed PMC

Novotna A, Petr P, Dvorak Z (2011) Novel Stably Transfected Gene Reporter Human Hepatoma Cell Line for Assessment of Aryl Hydrocarbon Receptor Transcriptional Activity: Construction and Characterization. Environmental Science & Technology 45: 10133–10139. PubMed

Novotna A, Pavek P, Dvorak Z (2012) Construction and characterization of a reporter gene cell line for assessment of human glucocorticoid receptor activation. European Journal of Pharmaceutical Sciences 47: 842–847. 10.1016/j.ejps.2012.10.003 PubMed DOI

Vrzal R, Knoppova B, Bachleda P, Dvorak Z (2013) Effects of oral anorexiant sibutramine on the expression of cytochromes P450s in human hepatocytes and cancer cell lines. J Biochem Mol Toxicol 27: 515–521. 10.1002/jbt.21516 PubMed DOI

Vavrova A, Vrzal R, Dvorak Z (2013) A nonradioactive electrophoretic mobility shift assay for measurement of pregnane X receptor binding activity to CYP3A4 response element. Electrophoresis 34: 1863–1868. PubMed

Doricakova A, Novotna A, Vrzal R, Pavek P, Dvorak Z (2013) The role of residues T248, Y249 and T422 in the function of human pregnane X receptor. Arch Toxicol 87: 291–301. 10.1007/s00204-012-0937-9 PubMed DOI

Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Molecular Pharmacology 56: 1329–1339. PubMed

Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. Journal of Clinical Investigation 102: 1016–1023. PubMed PMC

Meadowcroft AM, Williamson KM, Patterson JH, Hinderliter AL, Pieper JA (1999) The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology 39: 418–424. PubMed

Sekhar MC, Reddy PJC (2012) Influence of atorvastatin on the pharmacodynamic and pharmacokinetic activity of repaglinide in rats and rabbits. Molecular and Cellular Biochemistry 364: 159–164. 10.1007/s11010-011-1214-6 PubMed DOI

Lee CK, Choi JS, Choi DH (2015) Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors. Pharmacological Reports 67: 44–51. 10.1016/j.pharep.2014.08.005 PubMed DOI

Choi DH, Shin WG, Choi JS (2008) Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil. European Journal of Clinical Pharmacology 64: 445–449. 10.1007/s00228-007-0447-5 PubMed DOI

Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, et al. (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: Effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metabolism and Disposition 27: 410–416. PubMed

Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH (2000) Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos 21: 353–364. PubMed

Transon C, Leemann T, Dayer P (1996) In vitro comparative inhibition profiles of major human drug metabolising cytochrome p450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. European Journal of Clinical Pharmacology 50: 209–215. PubMed

Boralli VB, Coelho EB, Sampaio SA, Marques MP, Lanchote VL (2009) Enantioselectivity in the Pharmacokinetic Interaction Between Fluvastatin and Lercanidipine in Healthy Volunteers. Journal of Clinical Pharmacology 49: 205–211. 10.1177/0091270008327536 PubMed DOI

Di Pietro G, Coelho EB, Geleilete TM, Marques MP, Lanchote VL (2006) Chiral evaluation of fluvastatin in human plasma by high-performance liquid chromatography electrospray mass spectrometry. Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences 832: 256–261. PubMed

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. PubMed

Pascussi JM, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem MJ, Maurel P (2008) The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol 48: 1–32. PubMed

Garcia I, Fall Y, Gomez G (2012) Review of synthesis, biological assay, and QSAR studies of HMGR inhibitors. Curr Top Med Chem 12: 895–919. PubMed