-
1.
Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin.
Stopfer, P, Giessmann, T, Hohl, K, Sharma, A, Ishiguro, N, Taub, ME, Zimdahl-Gelling, H, Gansser, D, Wein, M, Ebner, T, et al
Clinical pharmacology and therapeutics. 2016;(3):259-67
-
-
Free full text
-
Abstract
This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P-gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2-K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six-period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0-tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0-tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter-mediated drug-drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.
-
2.
Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?
Birmingham, BK, Bujac, SR, Elsby, R, Azumaya, CT, Wei, C, Chen, Y, Mosqueda-Garcia, R, Ambrose, HJ
European journal of clinical pharmacology. 2015;(3):341-55
Abstract
PURPOSE Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. METHODS Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. RESULTS Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. CONCLUSION Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.
-
3.
High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.
Silbernagel, G, Chapman, MJ, Genser, B, Kleber, ME, Fauler, G, Scharnagl, H, Grammer, TB, Boehm, BO, Mäkelä, KM, Kähönen, M, et al
Journal of the American College of Cardiology. 2013;(4):291-9
Abstract
OBJECTIVES This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. CONCLUSIONS High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.
-
4.
ATP-binding cassette transporter G5 and G8 polymorphisms and several environmental factors with serum lipid levels.
Li, Q, Yin, RX, Wei, XL, Yan, TT, Aung, LH, Wu, DF, Wu, JZ, Lin, WX, Liu, CW, Pan, SL
PloS one. 2012;(5):e37972
Abstract
BACKGROUND The association of ATP-binding cassette (ABC) transporter single nucleotide polymorphisms (SNPs) and serum lipid profiles is inconsistent. The present study was undertaken to detect the association of ABCG5/G8 SNPs and several environmental factors with serum lipid levels. METHODOLOGY/PRINCIPAL FINDINGS Genotyping of the ABCG5 (rs4131229 and rs6720173) and ABCG8 (rs3806471 and rs4148211) SNPs was performed in 719 unrelated subjects of Mulao nationality and 782 participants of Han nationality. There were no differences in the genotypic and allelic frequencies of four SNPs between the two ethnic groups besides the genotypic frequencies of rs4131229 SNP in Han. The levels of triglyceride (TG), apolipoprotein (Apo) A1, and ApoA1/ApoB ratio (rs4131229); low-density lipoprotein cholesterol (LDL-C) and ApoB (rs6720173); high-density lipoprotein cholesterol (HDL-C), ApoA1, ApoB, and ApoA1/ApoB ratio (rs3806471); and HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han were different among their genotypes (P<0.05-0.001). The levels of LDL-C (rs6720173) and ApoA1 (rs3806471) in Mulao were also different among their genotypes (P<0.05 for each). The levels of TC, TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4131229); LDL-C and ApoB (rs6720173); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs3806471); and TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han males; and ApoA1/ApoB ratio (rs4131229); LDL-C, ApoB, and ApoA1/ApoB ratio (rs3806471); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han females were different between the genotypes (P<0.05-0.001). The levels of LDL-C in Mulao females were also different between GG and GC/CC genotypes of rs6720173 (P<0.05). The correlation between serum lipid parameters and genotypes of four SNPs was observed in Han, especially in Han males. Serum lipid parameters were also correlated with several environmental factors. CONCLUSIONS The associations of four ABCG5/G8 SNPs and serum lipid levels are different between the Mulao and Han populations, or between males and females, suggesting that there may be a racial/ethnic- and/or sex-specific association between ABCG5/G8 SNPs and some serum lipid parameters.
-
5.
ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin.
Tomlinson, B, Hu, M, Lee, VW, Lui, SS, Chu, TT, Poon, EW, Ko, GT, Baum, L, Tam, LS, Li, EK
Clinical pharmacology and therapeutics. 2010;(5):558-62
Abstract
The ATP-binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL-C level, in a gene-dose-dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL-C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.
-
6.
Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
Florez, JC, Jablonski, KA, Kahn, SE, Franks, PW, Dabelea, D, Hamman, RF, Knowler, WC, Nathan, DM, Altshuler, D
Diabetes. 2007;(2):531-6
-
-
Free full text
-
Abstract
The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over approximately 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
-
7.
The ABCG5 polymorphism contributes to individual responses to dietary cholesterol and carotenoids in eggs.
Herron, KL, McGrane, MM, Waters, D, Lofgren, IE, Clark, RM, Ordovas, JM, Fernandez, ML
The Journal of nutrition. 2006;(5):1161-5
-
-
Free full text
-
Abstract
The ATP binding cassette G5 (ABCG5) polymorphisms have been postulated to play a role in the response to dietary cholesterol. The objective of this study was to examine the contribution of the ABCG5 polymorphism on the plasma response to consumption of cholesterol and carotenoids from eggs. For this purpose, genotyping was conducted for 40 men and 51 premenopausal women who were randomly assigned to consume an egg (EGG, 640 mg/d additional dietary cholesterol and 600 microg lutein+ zeaxanthin) or placebo (SUB, 0 mg/d cholesterol, 0 microg lutein + zeaxanthin) diet for 30 d. The two arms of the dietary intervention were separated by a 3-wk washout period. Plasma concentrations of total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were determined. Because eggs are an excellent source of lutein and zeaxanthin, the plasma levels of these carotenoids were also measured in a subset of subjects to determine whether the response to carotenoid intake was similar to that seen for dietary cholesterol and to evaluate the contribution of ABCG5 polymorphism to both responses. Individuals possessing the C/C genotype experienced a greater increase in both LDL-C (P < 0.05) and a trend for lutein (P = 0.08) during the EGG period compared with those individuals with the C/G (heterozygote) or G/G genotypes (homozygotes). These results, although obtained from a small number of subjects, suggest that the ABCG5 polymorphism may play a role in the plasma response to dietary cholesterol and carotenoids.
-
8.
Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study.
Laukkanen, O, Pihlajamäki, J, Lindström, J, Eriksson, J, Valle, TT, Hämäläinen, H, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, Tuomilehto, J, Uusitupa, M, et al
The Journal of clinical endocrinology and metabolism. 2004;(12):6286-90
Abstract
Type 2 diabetes is caused by defective insulin secretion and impaired insulin action. We investigated whether common polymorphisms in the SUR1 and Kir6.2 genes are associated with increased risk of type 2 diabetes in 490 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study. The 1273AGA allele of the SUR1 gene was associated with a 2-fold risk of type 2 diabetes [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.19-3.36; P = 0.009]. This silent polymorphism was in linkage disequilibrium with three promoter polymorphisms (G-2886A, G-1561A, and A-1273G), and they formed a high-risk haplotype having a 2-fold risk of type 2 diabetes (OR, 1.89; 95% CI, 1.09-3.27; P = 0.023). Subjects with both the high-risk haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene had a 6-fold risk for the conversion to diabetes compared with those without any of these risk genotypes (OR, 5.68; 95% CI, 1.75-18.32; P = 0.004). We conclude that the polymorphisms of the SUR1 gene predicted the conversion from impaired glucose tolerance to type 2 diabetes and that the effect of these polymorphisms on diabetes risk was additive with the E23K polymorphism of the Kir6.2 gene.