Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Bailey, Kristian; Romaine, Simon P. R.; Jackson, B. M.; Farrin, Amanda; Efthymiou, Maria; Barth, Julian H.; Copeland, Joanne; McCormack, Terry; Whitehead, A. L.; Flather, Marcus; Samani, Nilesh J.; Nixon, John; Hall, Alistair S.; Balmforth, Anthony J.

doi:10.1161/circgenetics.109.898502

Cited by 95 publications

(55 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Genetic variants, including the SNPs at PCSK9, ABCG2, and APOE, have been shown to affect statin if not rosuvastatin response. 7,22 The association of SNP rs10455872 at the LPA locus with LDL-C lowering is probably related to a contribution of the cholesterol in lipoprotein (Lp)(a) particles to LDL-C measurements, 23 even though this same SNP was not strongly associated with baseline LDL-C in JUPITER (Figure 2). In separate data available to us, 24 SNP effects on plasma Lp(a) particle concentration at the LPA locus are highly correlated with weaker effects on plasma LDL-C (Spearman ϭ0.9) that may be not be manifest in JUPITER as a result of the LDL-C Ͻ130 mg/dL enrollment criterion.…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

Chasman

Giulianini

MacFadyen

et al. 2012

Circ Cardiovasc Genet

245

122

View full text Add to dashboard Cite

Background-In statin trials, each 20 mg/dL reduction in cholesterol results in a 10 -15% reduction of annual incidence rates for vascular events. However, interindividual variation in low-density lipoprotein cholesterol (LDL-C) response to statins is wide and may partially be determined on a genetic basis. Methods and Results-A genome-wide association study of LDL-C response was performed among a total of 6989 men and women of European ancestry who were randomly allocated to either rosuvastatin 20 mg daily or placebo. Single nucleotide polymorphisms (SNPs) for genome-wide association (PϽ5ϫ10 Ϫ8 ) with LDL-C reduction on rosuvastatin were identified at ABCG2, LPA, and APOE, and a further association at PCSK9 was genome-wide significant for baseline LDL-C and locus-wide significant for LDL-C reduction. Median LDL-C reductions on rosuvastatin were 40, 48, 51, 55, 60, and 64 mg/dL, respectively, among those inheriting increasing numbers of LDL-lowering alleles for SNPs at these 4 loci (P trendϭ6.2ϫ10 Ϫ20 ), such that each allele approximately doubled the odds of percent LDL-C reduction greater than the trial median (odds ratio, 1.9; 95% confidence interval, 1.8 -2.1; Pϭ5.0ϫ10 Ϫ41 ). An intriguing additional association with sub-genome-wide significance (PϽ1ϫ10 -6 ) was identified for statin related LDL-C reduction at IDOL, which mediates posttranscriptional regulation of the LDL receptor in response to intracellular cholesterol levels. In candidate analysis, SNPs in SLCO1B1 and LDLR were confirmed as associated with LDL-C lowering, and a significant interaction was observed between SNPs in PCSK9 and LDLR. Conclusions-Inherited polymorphisms that predominantly relate to statin pharmacokinetics and endocytosis of LDL particles by the LDL receptor are common in the general population and influence individual patient response to statin therapy. (Circ Cardiovasc Genet. 2012;5:257-264.)

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

Chasman

Giulianini

MacFadyen

et al. 2012

Circ Cardiovasc Genet

245

122

View full text Add to dashboard Cite

show abstract

“…Drug interactions with BCRP are less likely as a large fraction of BCRP substrates and inhibitors are chemotherapeutic agents [21]. However, unlike P-gp, there are common reduced function polymorphisms in BCRP (c.34 G>A, c.421 C>T) recognized for affecting the PK of its substrates [22,23]. Collectively, we postulate that homozygous carriers of BCRP variants concomitantly taking P-gp/CYP3A4 inhibitors likely possess the greatest risk for haemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Absence of both MDR1 (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Transporters Significantly Alters Rivaroxaban Disposition and Central Nervous System Entry

Gong

Mansell

Kim

2012

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Rivaroxaban is a novel factor 10a inhibitor, where hepatic metabolism and renal clearance account for its overall disposition. Renal impairment is known to increase rivaroxaban-associated bleeding risk in patients. As renal rivaroxaban clearance exceeds glomerular filtration rate, we suggested that active secretion by efflux transporters P-glycoprotein (MDR1) and breast cancer resistance protein (BCRP) contributes to rivaroxaban clearance. The ability of MDR1 and BCRP efflux transporters to mediate rivaroxaban transport in vitro was assessed in polarized cell monolayers. A significantly greater vectorial transport of rivaroxaban was observed in the basal to apical direction in Caco-2 cells, which was attenuated in the presence of the selective inhibitors. After oral administration of rivaroxaban (2 mg/kg), plasma concentrations did not significantly differ between wildtype and Mdr1a def or Bcrp À/À mice (n = 6 per group). However, rivaroxaban clearance was significantly reduced in Mdr1a/ Mdr1b À/À /Bcrp À/À mice. Interestingly, rivaroxaban brain-to-plasma ratio did not differ in mice lacking only Mdr1a or Bcrp, but more than two times higher in the Mdr1a/Mdr1b À/À /BcrpÀ/À mice. Rivaroxaban is a shared substrate of MDR1 and BCRP. In vivo, MDR and BCRP function synergistically to modulate rivaroxaban disposition and appear to be particularly relevant to limiting its central nervous system entry. These data have important implications for safety and efficacy of anticoagulation therapy with rivaroxaban as many drugs in clinical use are known MDR1 inhibitors and loss-of-function polymorphisms in BCRP are common.Thromboembolic events resulting from blood clotting disorders are a significant source of mortality and morbidity and thus often require life-long anticoagulation therapy [1]. Although warfarin has been the mainstay of therapy, important limitations in its use have prompted development of newer agents [2]. Rivaroxaban is a reversible factor 10a inhibitor recently approved for stroke prevention in atrial fibrillation (AF) patients and treatment of venous thromboembolism (VTE) [3].Rivaroxaban oral bioavailability was reported to be over 80% and achieves maximal anticoagulation 2-4 hr after administration [4]. Excretion of rivaroxaban occurs through two main pathways; cytochrome P450 (CYP) 2J2-and CYP3A4-dependent metabolism are responsible for two-thirds of its elimination, while one-third is renally excreted unchanged [4]. However, renal elimination may be greater than currently assumed as rivaroxaban exposure is 50% higher in patients with renal impairment [4]. Furthermore, bleeding complications were higher in patients with poor renal function [2,5]. Renal excretion appears to be greater than glomerular filtration rate, suggesting a significant contribution of active secretory processes to rivaroxaban elimination [2].There has been growing appreciation of drug transporters expressed in various tissues in determining the disposition and excretion of a wide range of xenobiotics [6]; P-glycoprotein (P...

show abstract

“…Consequently, these transporters can affect the efficacy (Bailey et al, 2010;Tomlinson et al, 2010) and toxicity (Alexandridis et al, 2000;Bosch Rovira et al, 2001;Marsa Carretero et al, 2002) of drugs by modulating their exposure to the target sites (Harwood et al, 2013). Hence, it is important to delineate the role of hepatic transporters in drug disposition and local tissue drug exposure, particularly because plasma drug concentrations are generally used as a surrogate measure of tissue concentrations to describe pharmacokineticpharmacodynamic relationships and to predict drug-drug interactions (DDIs) or drug-gene interactions (Lon et al, 2012;Harwood et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

et al. 2013

View full text Add to dashboard Cite

Interindividual variability in protein expression of organic aniontransporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean 6 S.D. (maximum/minimum range in parentheses) protein expression (

show abstract

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Cited by 95 publications

References 53 publications

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

Absence of both MDR1 (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Transporters Significantly Alters Rivaroxaban Disposition and Central Nervous System Entry

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

Contact Info

Product

Resources

About