title: In vitro risk assessment of AZD9056 perpetrating a transporter-mediated drug-drug interaction with methotrexate.
abstract: Methotrexate is the most commonly used drug to treat rheumatoid arthritis. Since clinical efficacy studies in rheumatoid arthritis are conducted on a background of methotrexate therapy, it is necessary to assess the potential of rheumatoid arthritis candidate drugs to perpetrate a drug-drug interaction (DDI) with methotrexate during development. Consequently, we need to identify the regulatory in vitro studies required to facilitate this assessment. We therefore reviewed the literature to ascertain the methotrexate disposition pathways implicated with known DDIs. Experiments were conducted to confirm that methotrexate was identified as a substrate for these pathways in our laboratory. The literature indicated active renal elimination (mediated by the human transporters OAT1, OAT3, MRP2 and BCRP) to be the principal pathway for methotrexate DDI risk. With the exception of MRP2, methotrexate was confirmed as a substrate of these transporters using oocyte and membrane vesicle test systems. A rheumatoid arthritis candidate drug (AZD9056) and sulfasalazine were subsequently assessed as inhibitors of OAT1, OAT3 and BCRP to determine their DDI potential towards methotrexate. AZD9056 was neither an inhibitor of OAT1 nor OAT3 and did not inhibit their transport of methotrexate. AZD9056 was an inhibitor of BCRP and weakly inhibited BCRP-mediated transport of methotrexate (IC(50)=92μM). Sulfasalazine inhibited methotrexate transport mediated by all transporters studied (IC(50)<5μM). Subsequent assessment of the in vitro data using [I]/IC(50) ratios indicated that both AZD9056 and sulfasalazine were unlikely to cause a DDI with methotrexate in vivo. In conclusion, to support rheumatoid arthritis drug development it is proposed that regulatory in vitro studies for OAT1, OAT3 and BCRP inhibition be routinely conducted to assess the potential for a transporter-mediated DDI with methotrexate in vivo.
authors: Clinical Pharmacology and DMPK, AstraZeneca Research & Development Charnwood, Loughborough, Leicestershire, United Kingdom. Robert.Elsby@astrazeneca.com
authors: Robert
authors: R
authors: Elsby
authors: Lisa
authors: L
authors: Fox
authors: David
authors: D
authors: Stresser
authors: Mark
authors: M
authors: Layton
authors: Caroline
authors: C
authors: Butters
authors: Pradeep
authors: P
authors: Sharma
authors: Veronica
authors: V
authors: Smith
authors: Dominic
authors: D
authors: Surry
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001692:Biological Transport / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D018570:Risk Assessment; D012460:Sulfasalazine / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D012460:Sulfasalazine; D008727:Methotrexate