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Pharmacokinetics, distribution, and metabolism of [14C]sunitinib in rats, monkeys, and humans

Bill Speed1, Hai-Zhi Bu, William F Pool

  • 1Pharmacokinetics, Dynamics & Metabolism, Sandwich, Kent, United Kingdom.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|December 20, 2011
PubMed

Insights

Sunitinib is extensively absorbed and metabolized, with the des-ethyl metabolite M1 being the primary circulating form across species. Elimination primarily occurs via feces, with longer half-lives observed in humans.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Toxicology

Background:

  • Sunitinib is an oral multitargeted tyrosine kinase inhibitor used for advanced renal cell carcinoma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors.
  • Understanding sunitinib's pharmacokinetic profile, distribution, and metabolism is crucial for its therapeutic application.

Purpose of the Study:

  • To characterize the pharmacokinetics, distribution, and metabolism of sunitinib in rats, monkeys, and humans.
  • To identify major metabolic pathways and circulating metabolites of sunitinib.

Main Methods:

  • Administration of radiolabeled [(14)C]sunitinib via intravenous and oral routes in rats, monkeys, and humans.
  • Analysis of plasma concentrations, elimination half-lives, excretion routes, and tissue distribution using whole-body autoradioluminography.
  • Identification of metabolites in urine and fecal extracts.

Main Results:

  • Sunitinib demonstrated high oral bioavailability (close to 100% in female rats) with peak plasma concentrations at 3-8 hours.
  • Plasma terminal elimination half-lives varied by species: 8 hours (rats), 17 hours (monkeys), and 51 hours (humans).
  • Excretion was predominantly via feces, with radioactivity cleared from most tissues within 72 hours, but slower elimination from pigmented tissues.

Conclusions:

  • Sunitinib is extensively metabolized in rats, monkeys, and humans, with N-de-ethylation and hydroxylation as primary pathways.
  • The des-ethyl metabolite M1 was identified as the major circulating metabolite in all three species.
  • Pharmacokinetic parameters, including elimination half-life, differ significantly across species, highlighting the importance of species-specific considerations.

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