title: Disposition of atorvastatin, rosuvastatin, and simvastatin in oatp1b2-/- mice and intraindividual variability in human subjects.
abstract: Response to statin therapy is often unpredictable because of variability in metabolism and transport. In the recently created organic anion transporting-polypeptide 1b2 (Oatp1b2/Slco1b2)-null mice, the investigators found significantly lower liver-to-plasma ratios compared with controls for atorvastatin (16.0 ± 5.1 vs 43.5 ± 13.7, P = .002) and rosuvastatin (15.2 ± 3.3 vs 28.4 ± 9.3, P = .03), but not simvastatin (5.2 ± 1.1 vs 6.3 ± 2.9, P = .49), following tail vein injection of 1 mg/kg of each drug. In addition, the investigators examined intraindividual variation in atorvastatin, rosuvastatin, and simvastatin pharmacokinetics in healthy human subjects in a crossover study design. Areas under the plasma concentration-time curve of atorvastatin and simvastatin acid were significantly related (Spearman r = 0.68; P = .035), whereas rosuvastatin profile was not related to atorvastatin or simvastatin exposure. Together, these results in mice and humans demonstrate that predictability of exposure to one statin based on another is dependent on the specific statin pairs and the context in which they are compared.
authors.affiliation: ALL-152 LHSC-University Hospital, 339 Windermere Road, London, Ontario, N6A 5A5 Canada. richard.kim@lhsc.on.ca
authors.forename: M K
authors.initials: MK
authors.lastname: DeGorter
authors.forename: B L
authors.initials: BL
authors.lastname: Urquhart
authors.forename: U
authors.initials: U
authors.lastname: Gradhand
authors.forename: R G
authors.initials: RG
authors.lastname: Tirona
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D019540:Area Under Curve; D000069059:Atorvastatin; D018592:Cross-Over Studies; D005260:Female; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics*; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D011743:Pyrimidines; D011758:Pyrroles; C498887:Slco1b2 protein, mouse; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin