Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy.
Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 (SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: -14.1 vs -28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7alpha-hydroxylase (CYP7A1) and apolipoprotein E (APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE epsilon4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (-24.3 vs -33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin.
Takane
Hiroshi
H
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Miyata
Masanori
M
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Japan.
Burioka
Naoto
N
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Japan.
Shigemasa
Chiaki
C
Division of Molecular Medicine and Therapeutics, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
Shimizu
Eiji
E
Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Japan.
Otsubo
Kenji
K
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Ieiri
Ichiro
I
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ieiri-ttr@umin.ac.jp.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008055:Lipids / Q000097:blood; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D017035:Pravastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D008055:Lipids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; D017035:Pravastatin