Absorption, Distribution, Metabolism, and Excretion of [ 14 C]-Sotorasib in Rats and Dogs: Interspecies Differences in Absorption, Protein Conjugation and Metabolism.

Autor:	Dahal UP; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California., Rock BM; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California., Rodgers J; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California., Shen X; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California., Wang Z; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California., Wahlstrom JL; Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California janw@amgen.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2022 May; Vol. 50 (5), pp. 600-612. Date of Electronic Publication: 2022 Feb 13.
DOI:	10.1124/dmd.121.000798
Abstrakt:	Sotorasib is a first-in-class, targeted covalent inhibitor of Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C approved by the FDA to treat patients with locally advanced or metastatic non-small cell lung cancer with the KRAS G12C mutation. The mass balance, excretion, and metabolism of [ 14 C]-sotorasib was characterized in rats and dogs after a single dose of 60 or 500 mg/kg, respectively. Mean recovery was >90% for both species. Excretion of unchanged sotorasib was a minor pathway in rats, accounting for <4% of administered dose in urine and <7% of administered dose in feces. Approximately 66% of administered dose was recovered in the bile from bile duct cannulated rats as metabolites. Excretion of unchanged sotorasib was the major excretion pathway in dogs, likely caused by solubility-limited absorption. Major pathways of sotorasib biotransformation included glutathione conjugation and oxidative metabolism. In vitro experiments demonstrated that nonenzymatic conjugation (Michael addition) was the primary mechanism of the reaction with glutathione. Extended radioactivity profiles in blood and plasma were observed in rats, but not dogs, after dosing with [ 14 C]-sotorasib. In vitro experiments demonstrated that sotorasib-protein adducts were observed with both rat hemoglobin and serum albumin, explaining the extended radioactivity profile. SIGNIFICANCE STATEMENT: This study characterized the mass balance, excretion, and metabolism of [ 14 C]-sotorasib, a covalent Kirsten rat sarcoma viral oncogene homolog G12C inhibitor, in rats and dogs. Rapid absorption and extensive metabolism of sotorasib was observed in rats, while sotorasib was primarily excreted unchanged in dog feces, likely due to solubility-limited absorption. Protein adducts with rat hemoglobin and serum albumin were characterized, explaining observed extended blood and plasma radioactivity profiles. The primary biotransformation pathway, glutathione conjugation, was mediated through nonenzymatic conjugation. (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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