title: Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice.
abstract: The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞and 2.2-fold higher AUC0→∞in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC0→∞ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0→∞(p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0→∞(p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.
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: Ming Hui
authors.initials: MH
authors.lastname: Liew
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: Salby
authors.initials: S
authors.lastname: Ng
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: Chii Chii
authors.initials: CC
authors.lastname: Chew
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: Teng Wai
authors.initials: TW
authors.lastname: Koo
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: Yun Lee
authors.initials: YL
authors.lastname: Chee
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: Evelyn Li-Ching
authors.initials: EL
authors.lastname: Chee
authors.affiliation: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Modamio
authors.affiliation: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fernández
authors.affiliation: Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, 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. segarra100@gmail.com.|Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, Spain. segarra100@gmail.com.|Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, Spain. segarra100@gmail.com.
authors.forename: Ignacio
authors.identifier: 0000-0002-8721-2393
authors.initials: I
authors.lastname: Segarra
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D000077210:Sunitinib
chemical_list: D018712:Analgesics, Non-Narcotic; D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000082:Acetaminophen; D000077210:Sunitinib
keywords: Blood-brain barrier; Brain tumor; Drug-drug interaction; Paracetamol; Sex-divergent pharmacokinetics; Sunitinib