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Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects.

ABSTRACT: Statins are effective agents in the primary and secondary prevention of cardiovascular disease, but treatment response to statins varies among individuals. We analyzed multiple genetic polymorphisms and assessed pharmacokinetic and lipid-lowering responses after atorvastatin 80 mg treatment in healthy Korean individuals.Atorvastatin 80 mg was given to 50 healthy Korean male volunteers. Blood samples were collected to measure plasma atorvastatin and lipid concentrations up to 48 hours after atorvastatin administration. Subjects were genotyped for 1,936 drug metabolism and transporter genetic polymorphisms using the Affymetrix DMET plus array.The pharmacokinetics and lipid-lowering effect of atorvastatin showed remarkable interindividual variation. Three polymorphisms in the SLCO1B1, SLCO1B3, and ABCC2 genes were associated with either the maximum concentration (Cmax) of atorvastatin or changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C). Minor homozygotes (76.5 ng/mL) of SLCO1B1 c.-910G>A showed higher Cmax than heterozygotes (34.0 ng/mL) and major homozygotes (33.5 ng/mL, false discovery rate P=0.040). Cmax and the area under the plasma concentration curve from hour 0 to infinity (AUC?) were higher in carriers of the SLCO1B1*17 haplotype that included c.-910G>A than in noncarriers (46.1 vs 32.8 ng/mL for Cmax; 221.5 vs 154.2 ng/mL for AUC?). SLCO1B3 c.334G>T homozygotes (63.0 ng/mL) also showed higher Cmax than heterozygotes (34.7 ng/mL) and major homozygotes (31.4 ng/mL, FDR P=0.037). A nonsynonymous ABCC2 c.1249G>A was associated with small total cholesterol and LDL-C responses (0.23% and -0.70% for G/A vs -11.9% and -17.4% for G/G). The Cmax tended to increase according to the increase in the number of minor allele of SLCO1B1 c. -910G>A and SLCO1B3 c.334G>T.Genetic polymorphisms in transporter genes, including SLCO1B1, SLCO1B3, and ABCC2, may influence the pharmacokinetics and lipid-lowering response to atorvastatin administration.

SUBMITTER: Woo HI

PROVIDER: S-EPMC5391214 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects.

Woo Hye In HI Kim Suk Ran SR Huh Wooseong W Ko Jae-Wook JW Lee Soo-Youn SY

Drug design, development and therapy 20170404

<h4>Background</h4>Statins are effective agents in the primary and secondary prevention of cardiovascular disease, but treatment response to statins varies among individuals. We analyzed multiple genetic polymorphisms and assessed pharmacokinetic and lipid-lowering responses after atorvastatin 80 mg treatment in healthy Korean individuals.<h4>Methods</h4>Atorvastatin 80 mg was given to 50 healthy Korean male volunteers. Blood samples were collected to measure plasma atorvastatin and lipid concen ...[more]

PMID: 28435225

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Project description:Migraine is one of the most common headache disorders that greatly affect the quality of life. Selective serotonin (5-HT) receptor agonists such as triptamine-based drugs called triptans are used for treatment of migraine.This study aimed to evaluate the pharmacokinetic (PK) and tolerability profiles of eletriptan hydrobromide (eletriptan HBr), a selective 5-hydroxytryptamine (also known as serotonin) 1B/1D receptor agonist, in Koreans and compare the results to those observed in non-Koreans in a previously published study.A randomized, open-label, single, and repeated-dose study was conducted in 16 healthy Korean male subjects using a four-treatment, four-period, and four-sequence crossover design (NCT01139515). The subjects received one of the following four treatments in each period: a single dose of 20, 40, 80 mg eletriptan HBr or a repeated oral dose of 40 mg 2 h apart. Blood samples were collected before and up to 26 h after dosing for quantification of plasma eletriptan concentration by high-performance liquid chromatography tandem-mass spectrometry. The PK parameters were estimated using noncompartmental methods. Ethnicity differences between Korean and non-Korean subjects were identified using geometric mean ratios and 90% confidence intervals (CIs) of dose-normalized maximum plasma concentration (Cmax) and dose-normalized area under the plasma concentration versus time curve from 0 h to the last measurable concentration (AUC0-t).After single-dose administration of eletriptan HBr to Korean subjects, the mean Cmax and AUC0-t increased linearly with dose. Comparable total systemic exposures were observed in the 2 h apart 40 mg repeated and single 80 mg dose. The geometric mean ratios (90% CIs) of the dose-normalized Cmax and AUC0-t of Korean subjects were similar to those of non-Korean subjects reported in the literature. The adverse events observed were transient and mild in severity.Eletriptan HBr showed linear PK and was well tolerated in Korean subjects. The PK and tolerability of eletriptan HBr did not differ between Korean and non-Korean subjects.

Project description:Abstract Objectives Genetic variation contributes to individual differences in food preference, dietary habit, and nutrient intake, thus affecting nutritional status. Although studies which showed the relevance between genetic differences and the intake of nutrients such as carotenoid, vitamin E, and fat are available, more studies are needed for implementation of precision nutrition. Objective of the study was to investigate genetic variations that are associated with nutrient intake and taste sensitivity. Methods A total of 100 healthy adults (50 men and 50 women) aged 25–35 y who were free of diseases were recruited. Anthropometric measurements, clinical parameters including CBC, lipid profile, glucose level, and liver function tests, dietary intake data using 3-day food record, and taste sensitivity for salty and sweet tastes were determined. A total of 800,000 single nucleotide polymorphisms (SNPs) were analyzed by Theragen Etex using Theragen Precision Medicine Research Array (PMRA) chips. Results A total of 577,164 qualified SNPs were analyzed and three SNPs that might have significant relevance with energy intake (rs75052357, rs1125186, rs73471118) were identified. Carriers of the C allele in rs75052357 (C > T), which is identified in IQGAP1 loci, showed significantly higher fat mass (CC: 16.16 ± 3.52 kg, TC: 14.26 ± 3.58 kg, TT: 12.43 ± 3.83 kg) and higher % body fat (CC: 25.68 ± 5.40%, TC: 22.79 ± 6.10%, TT: 20.60 ± 7.52%) despite a lower energy intake (CC: 1782.2 ± 445.5 kcal, TC: 2212.5 ± 424.1 kcal, TT: 2315.0 ± 892.6 kcal). Carriers of G allele in rs1125186 (G > C) had significantly higher fat mass (CC: 13.34 ± 16.22 kg, CG: 16.22 ± 3.48 kg, GG: 15.67 ± 3.63 kg) in spite of lower energy intake compared with CC carriers (CC: 2222.5 ± 515.9 kcal, CG: 1927.9 ± 452.6 kcal, GG: 1745.7 ± 476.7 kcal). Carriers of T allele in rs73471118 (C > T) had significantly higher energy intake (CC: 1815.5 ± 445.0 kcal, TC: 2726.5 ± 490.6 kcal), while having lower threshold for sweet taste (CC: 8.94 ± 8.51 g/L TC: 0.40 ± 0.00 g/L). Conclusions Novel SNPs showing associations between energy consumption and fat mass or sugar taste sensitivity have been identified. This finding can help developing personalized recommendation for energy intake, however, further studies to delineate the mechanisms are needed. Funding Sources Supported by Seoul National University Research Grant in 2018.

Dataset Information

Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects.

Publications

Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects.

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