title: An S-warfarin and AZD1981 interaction: in vitro and clinical pilot data suggest the N-deacetylated amino acid metabolite as the primary perpetrator.
abstract: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N-deacetylated AZD1981 is responsible for the observed interaction.
  
  
  
  The excretion and biotransformation of [14C]-AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice-daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed.
  
  
  
  The excretion balance study showed N-deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time-dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S-warfarin area under the plasma concentration-time curve increased, on average, 1.4-fold [95% confidence interval (CI) 1.22, 1.50] and 2.4-fold (95% CI 2.11, 2.64) after 100 mg (n = 13) and 400 mg (n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction.
  
  
  
  N-deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug-drug interactions, with weak time-dependent inhibition exacerbated by efficient hepatic uptake being the cause.
authors: Respiratory, Inflammation & Autoimmune Disease Department of DMPK, AstraZeneca R&D, Gothenburg, Sweden.
authors: Ken
authors: K
authors: Grime
authors: Respiratory, Inflammation & Autoimmune Disease Department of DMPK, AstraZeneca R&D, Gothenburg, Sweden.
authors: Rikard
authors: R
authors: Pehrson
authors: Drug Safety and Metabolism, AstraZeneca R&D, Gothenburg, Sweden.
authors: Pär
authors: P
authors: Nordell
authors: AstraZeneca Early Clinical Development, Gaithersburg, MD, USA.
authors: Michael
authors: M
authors: Gillen
authors: Quintiles Allergy, Respiratory, Infectious Diseases & Vaccines Therapeutic Science & Strategy Unit, Uppsala, Sweden.
authors: Wolfgang
authors: W
authors: Kühn
authors: Quintiles Drug Research Unit at Guy's Hospital, London, UK.
authors: Timothy
authors: T
authors: Mant
authors: Respiratory, Inflammation & Autoimmune Disease Department of DMPK, AstraZeneca R&D, Gothenburg, Sweden.
authors: Marie
authors: M
authors: Brännström
authors: Respiratory, Inflammation & Autoimmune Disease Department of DMPK, AstraZeneca R&D, Gothenburg, Sweden.
authors: Petter
authors: P
authors: Svanberg
authors: Drug Safety and Metabolism, AstraZeneca R&D, Gothenburg, Sweden.
authors: Barry
authors: B
authors: Jones
authors: Roche DMPK, Basel, Switzerland.
authors: Clive
authors: C
authors: Brealey
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D065729:Cytochrome P-450 CYP2C9 / Q000187:drug effects / Q000378:metabolism; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D010865:Pilot Projects; D013997:Time Factors; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000085:Acetates; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D007211:Indoles; C569518:AZD1981; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9
keywords: CYP; drug transporters; drug-drug interactions; hepatic; warfarin