Abstract
Sunitinib is an oral multitargeted tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma, imatinib-refractory gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumors. The current studies were conducted to characterize the pharmacokinetics, distribution, and metabolism of sunitinib after intravenous and/or oral administrations of [14C]sunitinib in rats (5 mg/kg i.v., 15 mg/kg p.o.), monkeys (6 mg/kg p.o.), and humans (50 mg p.o.). After oral administration, plasma concentration of sunitinib and total radioactivity peaked from 3 to 8 h. Plasma terminal elimination half-lives of sunitinib were 8 h in rats, 17 h in monkeys, and 51 h in humans. The majority of radioactivity was excreted to the feces with a smaller fraction of radioactivity excreted to urine in all three species. The bioavailability in female rats was close to 100%, suggesting complete absorption of sunitinib. Whole-body autoradioluminography suggested radioactivity was distributed throughout rat tissues, with the majority of radioactivity cleared within 72 h. Radioactivity was eliminated more slowly from pigmented tissues. Sunitinib was extensively metabolized in all species. Many metabolites were detected both in urine and fecal extracts. The main metabolic pathways were N-de-ethylation and hydroxylation of indolylidene/dimethylpyrrole. N-Oxidation/hydroxylation/desaturation/deamination of N,N′-diethylamine and oxidative defluorination were the minor metabolic pathways. Des-ethyl metabolite M1 was the major circulating metabolite in all three species.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
ABBREVIATIONS:
- HPLC
- high-performance liquid chromatography
- LC-MS/MS
- liquid chromatography/tandem mass spectrometry
- AUC
- area under the concentration
- IS
- internal standard
- ESI
- electrospray ionization
- P450
- cytochrome P450
- SU012487
- N,N-diethyl-2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl]amino]ethanamine oxide
- SU012662
- N-[2-(ethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
- SU014335
- N-(2-aminoethyl)-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
- PHA-782584
- N-(2-diethylaminoethyl)-5-[(Z)-(5-hydroxy-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
- PHA-77473
- N-(2-diethylaminoethyl)-5-[(5-fluoro-2-oxo-indolin-3-yl)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
- Received September 16, 2011.
- Accepted December 16, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|