title: HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms.
abstract: OBJECTIVE
  OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endobiotics and xenobiotics and have been reported to have functional single nucleotide polymorphisms (SNPs). We have assessed the substrate specificities of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir.
  
  
  METHODS
  SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopuslaevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed.
  
  
  RESULTS
  Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors, are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3.
  
  
  CONCLUSIONS
  These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.forename: Wai San
authors.initials: WS
authors.lastname: Kwan
authors.forename: Victoria
authors.initials: V
authors.lastname: Shallcross
authors.forename: Ammara
authors.initials: A
authors.lastname: Chaikan
authors.forename: Neill
authors.initials: N
authors.lastname: Liptrott
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.forename: Enrique Salcedo
authors.initials: ES
authors.lastname: Sora
authors.forename: Chloë E
authors.initials: CE
authors.lastname: James
authors.forename: Sara
authors.initials: S
authors.lastname: Gibbons
authors.forename: Pat G
authors.initials: PG
authors.lastname: Bray
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003001:Cloning, Molecular; D016903:Drug Monitoring; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000187:drug effects; D011744:Pyrimidinones / Q000097:blood* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012042:Registries; D019438:Ritonavir / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity / Q000187:drug effects; D014981:Xenopus; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011744:Pyrimidinones; D012333:RNA, Messenger; C512988:SLCO1A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D061466:Lopinavir; D004970:Estrone; D019438:Ritonavir; C017296:estrone sulfate