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

• Published in: Drug design, development and therapy Vol. 11; pp. 1135 - 1146
• Main Authors: Woo, Hye In, Kim, Suk Ran, Huh, Wooseong, Ko, Jae-Wook, Lee, Soo-Youn
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 2017; Taylor & Francis Ltd; Dove Medical Press
• Subjects: ABCC2; Administration, Oral; Adult; Arrays; Atorvastatin; Atorvastatin Calcium - administration & dosage; Atorvastatin Calcium - metabolism; Atorvastatin Calcium - pharmacokinetics; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Deoxyribonucleic acid; DNA; Drug dosages; Drug metabolism; Enzymes; Family medical history; Female; Genes; Genetic aspects; Genetic diversity; Genetic polymorphisms; Genetic testing; Genetic Variation - genetics; Genomics; Genotype; Haplotypes; Health aspects; Healthy Volunteers; Heterozygotes; Homozygotes; Humans; Laboratories; Lipids; Lipids - blood; Lipoproteins; Low density lipoprotein; Male; Medical treatment; Medicine; Metabolism; Multidrug Resistance-Associated Proteins - genetics; Original Research; Patient outcomes; pharmacogenomics; Pharmacokinetics; Pharmacology; Polymorphism, Genetic - genetics; Polypeptides; Proteins; Republic of Korea; SLCO1B1; SLCO1B3; Software; Solute Carrier Organic Anion Transporter Family Member 1b1 - genetics; Solute Carrier Organic Anion Transporter Family Member 1B3 - genetics; Statins; Triglycerides; Variance analysis; Young Adult; South Korea; United States > US; pharmacokinetics; SLCO1B1; ABCC2; pharmacogenomics; atorvastatin; SLCO1B3
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S131487

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 , , and genes were associated with either the maximum concentration (C ) of atorvastatin or changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C). Minor homozygotes (76.5 ng/mL) of c.-910G>A showed higher C than heterozygotes (34.0 ng/mL) and major homozygotes (33.5 ng/mL, false discovery rate =0.040). C and the area under the plasma concentration curve from hour 0 to infinity (AUC ) were higher in carriers of the *17 haplotype that included c.-910G>A than in noncarriers (46.1 vs 32.8 ng/mL for C ; 221.5 vs 154.2 ng/mL for AUC ). c.334G>T homozygotes (63.0 ng/mL) also showed higher C than heterozygotes (34.7 ng/mL) and major homozygotes (31.4 ng/mL, FDR =0.037). A nonsynonymous 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 C tended to increase according to the increase in the number of minor allele of c. -910G>A and c.334G>T. Genetic polymorphisms in transporter genes, including , , and , may influence the pharmacokinetics and lipid-lowering response to atorvastatin administration.