Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.
Zhou Z, Rahme E, Pilote L (2006) Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 151: 273–281.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366: 1267–1278.
Ji Y, Hebbring S, Zhu H, Jenkins GD, Biernacka J, et al. (2011) Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89: 97–104.
Kaddurah-Daouk R, Boyle SH, Matson W, Sharma S, Matson S, et al. (2011) Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept. Transl Psychiatry 1: e26.
Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 106: 14728–14733.
Xiang X, Han Y, Neuvonen M, Pasanen MK, Kalliokoski A, et al. (2009) Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans. Pharmacogenet Genomics 19: 447–457.
Veiga P, Juste C, Lepercq P, Saunier K, Beguet F, et al. (2005) Correlation between faecal microbial community structure and cholesterol-to-coprostanol conversion in the human gut. FEMS Microbiol Lett 242: 81–86.
Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112: 71–105.
Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, et al. (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33: 537–546.
Chen C, Lin J, Smolarek T, Tremaine L (2007) P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice. Drug Metab Dispos 35: 1725–1729.
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.
Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, et al. (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274: 37161–37168.
Yamasaki D, Nakamura T, Okamura N, Kokudai M, Inui N, 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.
Tazuma S, Kajiyama G, Mizuno T, Yamashita G, Miura H, et al. (1998) A combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than is ursodeoxycholic acid monotherapy. J Clin Gastroenterol 26: 287–291.
Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, et al. (2006) Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol 97: 843–850.
Phillips KM, Ruggio DM, Bailey JA (1999) Precise quantitative determination of phytosterols, stanols, and cholesterol metabolites in human serum by capillary gas-liquid chromatography. J Chromatogr B Biomed Sci Appl 732: 17–29.
Tagliacozzi D, Mozzi AF, Casetta B, Bertucci P, Bernardini S, et al. (2003) Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: a simple and rapid one-step method. Clin Chem Lab Med 41: 1633–1641.
Burkard I, von Eckardstein A, Rentsch KM (2005) Differentiated quantification of human bile acids in serum by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 826: 147–159.
Zhao JJ, Xie IH, Yang AY, Roadcap BA, Rogers JD (2000) Quantitation of simvastatin and its beta-hydroxy acid in human plasma by liquid-liquid cartridge extraction and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 35: 1133–1143.