title: Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.
abstract: Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences.
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Christine Li Ling
authors.initials: CL
authors.lastname: Lau
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Sook Tyng
authors.initials: ST
authors.lastname: Chan
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Manimegahlai
authors.initials: M
authors.lastname: Selvaratanam
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Hui Wen
authors.initials: HW
authors.lastname: Khoo
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Adeline Yi Ling
authors.initials: AY
authors.lastname: Lim
authors.affiliation: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Modamio
authors.affiliation: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain.
authors.forename: Eduardo L
authors.initials: EL
authors.lastname: Mariño
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Segarra
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D007052:Ibuprofen / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012727:Sex Characteristics; D000077210:Sunitinib; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib; D007052:Ibuprofen
keywords: NSAID; blood-brain barrier; drug-drug interaction; ibuprofen; sunitinib; tissue distribution