title: Sunitinib tissue distribution changes after coadministration with ketoconazole in mice.
abstract: Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p < 0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61 %, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p < 0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4 ± 4.7; p < 0.001), kidney (17.1 ± 2.2; p > 0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.
authors: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
authors: Evelyn Li-Ching
authors: EL
authors: Chee
authors: Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.|Department of Medicine, Alfred Hospital, 55 Commercial Road, Prahran, VIC, 3181, Australia.
authors: Adeline Yi Ling
authors: AY
authors: Lim
authors: 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: Pilar
authors: P
authors: Modamio
authors: 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: Cecilia
authors: C
authors: Fernandez-Lastra
authors: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia. segarra100@gmail.com.|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. segarra100@gmail.com.|, C/Sant Albert 4, Valldoreix, 08197, Barcelona, Spain. segarra100@gmail.com.
authors: Ignacio
authors: I
authors: Segarra
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage; D019540:Area Under Curve; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D007211:Indoles / Q000008:administration & dosage* / Q000378:metabolism*; D007654:Ketoconazole / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000378:metabolism*; D000077210:Sunitinib; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D007654:Ketoconazole; D000077210:Sunitinib
keywords: Blood–brain barrier; Brain tissue distribution; Drug–drug interaction; Ketoconazole; Sunitinib
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