title: SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin.
abstract: OBJECTIVE
  Pravastatin is a hydrophilic substrate and fluvastatin a lipophilic substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 encoded by SLCO1B1. Our aim was to compare the effects of SLCO1B1 polymorphism on the pharmacokinetics of pravastatin and fluvastatin.
  
  
  METHODS
  We recruited 4 healthy volunteers (3 men and 1 woman) with the homozygous SLCO1B1 c.521CC genotype, 12 (7 men and 5 women) with the heterozygous c.521TC genotype, and 16 (8 men and 8 women) with the homozygous c.521TT genotype (control subjects). In a crossover study each subject ingested a single 40-mg dose of fluvastatin and pravastatin with a washout period of at least 1 week. Plasma fluvastatin and pravastatin concentrations were measured for 12 hours.
  
  
  RESULTS
  In men with the c.521CC genotype, the mean peak concentration in plasma and area under the plasma concentration-time curve from time 0 to infinity of pravastatin were 274% (95% confidence interval [CI], 92%-456%; P = .001) and 232% (95% CI, 74%-391%; P = .002) greater than those in men with the c.521TT genotype and 120% (95% CI, 11%-230%; P = .026) and 102% (95% CI, 3%-200%; P = .040) greater than those in men with the c.521TC genotype. In addition, women with the c.521TT genotype had a 147% (95% CI, 12%-281%; P = .028) greater peak concentration in plasma and a 142% (95% CI, 7%-242%; P = .034) greater area under the plasma concentration-time curve from time 0 to infinity than men with the c.521TT genotype. The pharmacokinetic variables of pravastatin were approximately similar among women with different SLCO1B1 genotypes. No significant differences were seen in the pharmacokinetics of fluvastatin between subjects with different SLCO1B1 genotypes or between the sexes.
  
  
  CONCLUSIONS
  SLCO1B1 polymorphism has a large effect on the pharmacokinetics of pravastatin but not fluvastatin. This suggests that the lipophilic fluvastatin can penetrate the hepatocyte plasma membrane via passive diffusion or that uptake transporters other than organic anion transporting polypeptide 1B1 mainly mediate its hepatic uptake. Moreover, the results suggest that sex may affect the pharmacokinetics of pravastatin and possibly the functional consequences of SLCO1B1 polymorphism.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland. mikko.niemi@hus.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Marja K
authors.initials: MK
authors.lastname: Pasanen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D005229:Fatty Acids, Monounsaturated / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D000077340:Fluvastatin; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D012016:Reference Values; D012727:Sex Characteristics; D012737:Sex Factors
chemical_list: D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077340:Fluvastatin; D017035:Pravastatin