Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17.
OBJECTIVE
The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake transporter OATP1B1, influence the short-term effects of pravastatin on cholesterol synthesis.


METHODS
We determined plasma concentrations of lathosterol and cholesterol up to 12 h after intake of a single dose of 40 mg pravastatin in 41 healthy Caucasian subjects, in whom SLCO1B1 single nucleotide polymorphisms (SNP; 521T>C and -11187G>A) and haplotypes (*15B and *17) had been previously shown to be associated with considerably elevated plasma pravastatin levels.


RESULTS
The effects of pravastatin on plasma lathosterol concentration and lathosterol to cholesterol concentration ratio, which are established markers of the rate of cholesterol synthesis in vivo, were significantly smaller among the three heterozygous carriers of the SLCO1B1 *17 haplotype (containing the -11187G>A, 388A>G and 521T>C SNPs) as compared with non-carriers. Significant inverse relationships were found between pravastatin area under the concentration-time curve (AUC) values and effects of pravastatin on lathosterol and lathosterol to cholesterol ratio among the whole study population.


CONCLUSIONS
These results suggest that uptake of pravastatin into hepatocytes is impaired in carriers of the SLCO1B1 haplotype *17, resulting in higher plasma pravastatin concentrations but lower concentrations of pravastatin in hepatocytes and thereby in a smaller inhibitory effect on cholesterol synthesis. The cholesterol-lowering response to pravastatin may be impaired in carriers of the *17 haplotype.
Niemi
Mikko
M
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Neuvonen
Pertti J
PJ
Hofmann
Ute
U
Backman
Janne T
JT
Schwab
Matthias
M
Lütjohann
Dieter
D
von Bergmann
Klaus
K
Eichelbaum
Michel
M
Kivistö
Kari T
KT
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D006239:Haplotypes; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C001521:lathosterol; D002784:Cholesterol; D017035:Pravastatin