title: SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid.
abstract: OBJECTIVE
  Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study.
  
  
  METHODS
  Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h.
  
  
  RESULTS
  In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0-24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone.
  
  
  CONCLUSIONS
  SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.forename: Juha
authors.initials: J
authors.lastname: Vakkilainen
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008148:Lovastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D008148:Lovastatin