title: Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy.
abstract: BACKGROUND
  The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls.
  
  
  METHODS
  A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls.
  
  
  RESULTS
  No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites atorvastatin lactone (P<.01) and p-hydroxyatorvastatin (P<.01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups.
  
  
  CONCLUSIONS
  This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, and Lipid Clinic, Rikshospitalet, Norway. monica.hermann@farmasi.uio.no
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bogsrud
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
authors.forename: Anders
authors.initials: A
authors.lastname: Asberg
authors.forename: Beata U
authors.initials: BU
authors.lastname: Mohebi
authors.forename: Leiv
authors.initials: L
authors.lastname: Ose
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069059:Atorvastatin; D016022:Case-Control Studies; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D005838:Genotype; D006538:Heptanoic Acids / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007783:Lactones / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D007783:Lactones; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; D003404:Creatinine; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D003402:Creatine Kinase