title: Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism.
abstract: BACKGROUND
  Organic anion transporting polypeptides (OATPs) are emerging as major determinants of pharmacokinetics for numerous drugs, with the 1B1 isoform-mediating hepatic uptake. The 521 T>C polymorphism has been correlated earlier with higher plasma concentrations of several drugs and the aim of this study was to determine whether this polymorphism influences trough concentrations of maraviroc.
  
  
  METHODS
  The uptake of maraviroc by OATP1B1 was assessed using a heterologous Xenopus laevis oocyte expression system and quantified using a novel liquid chromatography-mass spectrometry method. Regression analyses were conducted to identify factors associated with maraviroc Ctrough in 59 patients treated with maraviroc at 150, 300, or 600 mg twice daily.
  
  
  RESULTS
  Maraviroc was identified as a substrate for OATP1B1 with a Km of 33.9 μmol/l. A dose of 600 mg of etravirine or efavirenz [odds ratio (OR) = 0.22, 95% confidence interval (95% CI): 0.06-0.76; P = 0.016] and SLCO1B1 521 heterozygosity were both associated with maraviroc Ctrough, above the suggested target concentration of 50 ng/ml (OR = 20.3, 95% CI: 2.2-182; P = 0.007).
  
  
  CONCLUSIONS
  These findings show the importance of OATP1B1 for variability in maraviroc pharmacokinetics. Furthermore, the SLCO1B1 521 T>C polymorphism maybe useful in predicting higher plasma concentrations but these data should be confirmed before prospective clinical studies to define the clinical usefulness.
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy. marco.siccardi@unito.it
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Silvia
authors.initials: S
authors.lastname: Nozza
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.forename: Lorena
authors.initials: L
authors.lastname: Baietto
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Stefani
authors.forename: Darren
authors.initials: D
authors.lastname: Moss
authors.forename: Wai-San
authors.initials: WS
authors.lastname: Kwan
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002853:Chromatography, Liquid; D003510:Cyclohexanes / Q000097:blood* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D000077592:Maraviroc; D013058:Mass Spectrometry; D008875:Middle Aged; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects; D014230:Triazoles / Q000097:blood* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D003510:Cyclohexanes; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D014230:Triazoles; D000077592:Maraviroc