title: Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin.
abstract: OBJECTIVE
  Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters.
  
  
  METHODS
  The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems.
  
  
  RESULTS
  Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3.
  
  
  CONCLUSIONS
  The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.forename: Stephanie O
authors.initials: SO
authors.lastname: Klopfer
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.forename: Prajakti A
authors.initials: PA
authors.lastname: Kothare
authors.forename: Cynthia
authors.initials: C
authors.lastname: Dempsey
authors.forename: Scott
authors.initials: S
authors.lastname: Rasmussen
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Cai
authors.forename: Robert
authors.initials: R
authors.lastname: Valesky
authors.forename: Iain P
authors.initials: IP
authors.lastname: Fraser
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011743:Pyrimidines; D011804:Quinolines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C108475:pitavastatin; D012293:Rifampin
keywords: breast cancer resistance protein; drug-drug interactions; organic anion-transporting polypeptide 1B; pitavastatin; regulatory guidance; rosuvastatin