title: Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide.
abstract: OBJECTIVE
  Many tyrosine kinase inhibitors (TKI) undergo extensive hepatic metabolism, but mechanisms of their hepatocellular uptake remain poorly understood. We hypothesized that liver uptake of TKIs is mediated by the solute carriers OATP1B1 and OATP1B3.
  
  
  METHODS
  Transport of crizotinib, dasatinib, gefitinib, imatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib was studied in vitro using artificial membranes (PAMPA) and HEK293 cell lines stably transfected with OATP1B1, OATP1B3, or the ortholog mouse transporter, Oatp1b2. Pharmacokinetic studies were conducted with Oatp1b2-knockout mice and humanized OATP1B1- or OATP1B3-transgenic mice.
  
  
  RESULTS
  All 10 TKIs were identified as substrates of OATP1B1, OATP1B3, or both. Transport of sorafenib was investigated further, as its diffusion was particularly low in the PAMPA assay (<4%) than other TKIs that were transported by both OATP1B1 and OATP1B3. Whereas Oatp1b2 deficiency in vivo had minimal influence on parent and active metabolite N-oxide drug exposure, plasma levels of the glucuronic acid metabolite of sorafenib (sorafenib-glucuronide) were increased more than 8-fold in Oatp1b2-knockout mice. This finding was unrelated to possible changes in intrinsic metabolic capacity for sorafenib-glucuronide formation in hepatic or intestinal microsomes ex vivo. Ensuing experiments revealed that sorafenib-glucuronide was itself a transported substrate of Oatp1b2 (17.5-fold vs. control), OATP1B1 (10.6-fold), and OATP1B3 (6.4-fold), and introduction of the human transporters in Oatp1b2-knockout mice provided partial restoration of function.
  
  
  CONCLUSIONS
  These findings signify a unique role for OATP1B1 and OATP1B3 in the elimination of sorafenib-glucuronide and suggest a role for these transporters in the in vivo handling of glucuronic acid conjugates of drugs.
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Eric I
authors: EI
authors: Zimmerman
authors: Shuiying
authors: S
authors: Hu
authors: Justin L
authors: JL
authors: Roberts
authors: Alice A
authors: AA
authors: Gibson
authors: Shelley J
authors: SJ
authors: Orwick
authors: Lie
authors: L
authors: Li
authors: Alex
authors: A
authors: Sparreboom
authors: Sharyn D
authors: SD
authors: Baker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D020723:Glucuronic Acid / Q000097:blood; D057809:HEK293 Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010671:Phenylurea Compounds; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C498887:Slco1b2 protein, mouse; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D009536:Niacinamide; D020723:Glucuronic Acid; D000077157:Sorafenib