title: Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
abstract: BACKGROUND
  A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients.
  
  
  RESULTS
  In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (P<0.001) and ABCG2 c.421C>A (P<0.01) were important to rosuvastatin concentration (adjusted R(2)=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (P<0.01) and c.521T>C (P<0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R(2)=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile.
  
  
  CONCLUSIONS
  Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy.
authors.affiliation: Department of Medicine, The University of Western Ontario, London, Canada.
authors.forename: Marianne K
authors.initials: MK
authors.lastname: DeGorter
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Ute I
authors.initials: UI
authors.lastname: Schwarz
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: George K
authors.initials: GK
authors.lastname: Dresser
authors.forename: Neville
authors.initials: N
authors.lastname: Suskin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Myers
authors.forename: GuangYong
authors.initials: G
authors.lastname: Zou
authors.forename: Otito
authors.initials: O
authors.lastname: Iwuchukwu
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Wei
authors.forename: Russell A
authors.initials: RA
authors.lastname: Wilke
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005838:Genotype; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy*; D016014:Linear Models; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012189:Retrospective Studies; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C099828:cholest-5-ene-3,4-diol; C001521:lathosterol; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D000069059:Atorvastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A
keywords: ATP-binding cassette transporters; hydroxymethylglutaryl-CoA reductase inhibitors; organic anion transporters, sodium-independent; pharmacogenetics; pharmacokinetics