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.

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

“…Moreover, the synergy between sunitinib and erlotinib predicts even more potency in combination. Although sunitinib and erlotinib were largely cleared from the serum by 18 hours, which is in contrast with the slower clearance rates reported in humans (44,45), both drugs concentrate severalfold within tissues where DENV replicates, such as liver (46,47). To maintain higher serum drug concentration, we next administered 30 mg/kg drug combination at 12-hour intervals and measured viremia.…”

Synergistic Effect of Perampanel and Temozolomide in Human Glioma Cell Lines

“…Although the concentration of perampanel used in our experiments is higher than the steady-state plasmatic concentration in patients with epilepsy (about 5 µM), several factors may create and maintain disequilibrium between the drug concentration in plasma and tissues, leading to drug concentration asymmetry [ 26 ]. Active uptake may be greater than efflux and other elimination mechanisms in the tissue, resulting in local concentrations that may be higher than those of plasma, as described in brain tissue for sunitinib and diazepam, for example [ 27 , 28 ].…”

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma

“…Ketoconazole is a well-established inhibitor of 3A4. The in-vivo bioavailability of Sunitinib when co-administrated with Ketoconazole was described by Chee et al 38 After co-administration, an increase of sunitinib’s AUC plasma was seen. However, the dule drug’s AUC tissue to AUC plasma ratio within the kidney was found to be comparable to Sunitinib treatment alone.…”