title: In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters.
abstract: OBJECTIVE
  Lesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major liver and kidney transporters in vitro and evaluated the drug-drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies.
  
  
  METHODS
  Lesinurad interaction with membrane transporters was evaluated in validated transporter-expressing cell systems and analyzed by liquid scintillation counting. Healthy male subjects (ages 18-65 years; body mass index 18-32 kg/m(2)) received atorvastatin (40 mg; n = 28) with or without lesinurad 200 or 400 mg, or received metformin (850 mg; n = 12) or furosemide (40 mg; n = 11) with or without lesinurad 400 mg. Plasma concentrations of each concomitant drug were determined by validated liquid chromatography with tandem mass spectrometry methods.
  
  
  RESULTS
  Lesinurad interacted in vitro with OATP1B1, OCT1, and OAT1/3 transporters. Co-administration of lesinurad 200 mg did not significantly alter plasma exposure (maximum concentration [C max] and area under the concentration-time curve [AUC]) of total atorvastatin (atorvastatin + hydroxyl-metabolites) or atorvastatin, while co-administration of lesinurad 400 mg increased the C max of total atorvastatin and atorvastatin by 17-26 %, but had no effect on AUC. Co-administration of lesinurad 400 mg had no effect on the plasma exposure of metformin. Furosemide plasma AUC was reduced by 31 % in the presence of lesinurad 400 mg, but furosemide renal clearance and diuretic activity were unchanged.
  
  
  CONCLUSIONS
  No clinically relevant DDIs were observed between lesinurad and substrates of major liver or kidney transporters.
authors.affiliation: Translational Sciences, Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA. ZShen@ardeabio.com.
authors.forename: Zancong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Translational Sciences, Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.affiliation: Translational Sciences, Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wallach
authors.affiliation: Translational Sciences, Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Nanqun
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Translational Sciences, Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Kerr
authors.affiliation: AstraZeneca LP, One MedImmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000069059:Atorvastatin / Q000009:adverse effects; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D004232:Diuretics / Q000009:adverse effects; D004347:Drug Interactions; D005665:Furosemide / Q000009:adverse effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000009:adverse effects; D008875:Middle Aged; D013864:Thioglycolates / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014527:Uric Acid / Q000378:metabolism*; D014528:Uricosuric Agents / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D004232:Diuretics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D013864:Thioglycolates; D014230:Triazoles; D014528:Uricosuric Agents; C000593471:lesinurad; D014527:Uric Acid; D005665:Furosemide; D008687:Metformin; D000069059:Atorvastatin