title: Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice.
abstract: Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features.
  
  
  
  Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed.
  
  
  
  Ibuprofen halved sunitinib plasma concentration in female mice (p < 0.01) and showed 59 % lower concentration than male mice (p < 0.05). Diclofenac and paracetamol female mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p < 0.05) liver and 1.4-fold (p < 0.05) kidney sunitinib concentrations in male mice that were lower in female mice (p < 0.01, p < 0.001, respectively). Ibuprofen increased 2.9-fold (p < 0.01) liver concentration in male mice that were higher than in female mice (p < 0.001). Female control mice had 35 % higher sunitinib brain concentration than male mice but the concentration decreased 37, 33, 10 and 57 % in the diclofenac, paracetamol, mefenamic acid and ibuprofen (p < 0.001), respectively. Tissue-plasma concentrations correlations were nonsignificant in control, paracetamol, mefenamic acid and ibuprofen groups but was significant in the diclofenac group in male mice (liver, brain) and female mice (liver, kidney).
  
  
  
  These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Siok Yean
authors: SY
authors: Tan
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Mei Mei
authors: MM
authors: Wong
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Angela Lu Wun
authors: AL
authors: Tiew
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Yai Wen
authors: YW
authors: Choo
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Suat Hun
authors: SH
authors: Lim
authors: Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
authors: Ing Hong
authors: IH
authors: Ooi
authors: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors: Pilar
authors: P
authors: Modamio
authors: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors: Cecilia
authors: C
authors: Fernández
authors: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors: Eduardo L
authors: EL
authors: Mariño
authors: Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia. segarra100@gmail.com.|Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain. segarra100@gmail.com.|University of Barcelona, Avn Joan XXIII s/n, 08028, Barcelona, Spain. segarra100@gmail.com.
authors: Ignacio
authors: I
authors: Segarra
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007052:Ibuprofen / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D011758:Pyrroles / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D000077210:Sunitinib; D014018:Tissue Distribution
chemical_list: D018712:Analgesics, Non-Narcotic; D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D007211:Indoles; D011758:Pyrroles; D004008:Diclofenac; D000082:Acetaminophen; D008528:Mefenamic Acid; D000077210:Sunitinib; D007052:Ibuprofen
keywords: Diclofenac; Ibuprofen; Mefenamic acid; Paracetamol; Sex-divergent pharmacokinetics; Sunitinib