title: Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.
abstract: Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0.001). However, AUC0→∞remained unchanged in plasma and increased 41% in kidney (p < 0.001) of female mice. In brain, sunitinib exposure decreased 46% (p < 0.001) and 32% (p < 0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p < 0.05) and female (48%, p < 0.001) mice and 30% in kidney (p < 0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.
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: 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: 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: 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: 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: 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, Av. 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, Av. 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, Av. 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, Av. Joan XXIII s/n, 08028, Barcelona, Spain. segarra100@gmail.com.|cC/ Sant Albert 4, 08197, Valldoreix, Barcelona, Spain. segarra100@gmail.com.
authors.forename: Ignacio
authors.identifier: 0000-0002-8721-2393
authors.initials: I
authors.lastname: Segarra
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology*; 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; D014018:Tissue Distribution
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D004008:Diclofenac; D000077210:Sunitinib
keywords: Blood brain barrier; Diclofenac; Drug-drug interaction; Sex-divergent pharmacokinetics; Sunitinib