title: UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone.
abstract: BACKGROUND
  Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels.
  
  
  METHODS
  DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing.
  
  
  RESULTS
  Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6 .
  
  
  CONCLUSIONS
  The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Nydalen, P.O. Box 4956, 0424, Oslo, Norway. camilla.stormo@medisin.uio.no
authors.forename: Camilla
authors.initials: C
authors.lastname: Stormo
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bogsrud
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
authors.forename: Anders
authors.initials: A
authors.lastname: Åsberg
authors.forename: Armin P
authors.initials: AP
authors.lastname: Piehler
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Kringen
mesh_terms: D000328:Adult; D000483:Alleles; D000069059:Atorvastatin; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D000099148:UGT1A1 Enzyme
chemical_list: D000069059:Atorvastatin; D014453:Glucuronosyltransferase; D006538:Heptanoic Acids; D007783:Lactones; D011758:Pyrroles; D000099148:UGT1A1 Enzyme