PT  - JOURNAL ARTICLE
AU  - Bill Speed
AU  - Hai-Zhi Bu
AU  - William F. Pool
AU  - Geoffrey W. Peng
AU  - Ellen Y. Wu
AU  - Shem Patyna
AU  - Carlo Bello
AU  - Ping Kang
TI  - Pharmacokinetics, Distribution, and Metabolism of [<sup>14</sup>C]Sunitinib in Rats, Monkeys, and Humans
AID  - 10.1124/dmd.111.042853
DP  - 2012 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 539--555
VI  - 40
IP  - 3
4099  - http://dmd.aspetjournals.org/content/40/3/539.short
4100  - http://dmd.aspetjournals.org/content/40/3/539.full
SO  - Drug Metab Dispos2012 Mar 01; 40
AB  - 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.