Received for publication October 13, 2005.
Revised December 16, 2005.
Accepted for publication December 19, 2005.

METABOLISM AND EXCRETION OF ERLOTINIB, A SMALL MOLECULE INHIBITOR OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE, IN HEALTHY MALE VOLUNTEERS

Abstract

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers following a single oral dose of [¹⁴C]erlotinib hydrochloride (100 mg free base equivalent, ~91 µCi/subject). The mass balance was achieved with ~91% of the administered dose recovered in urine and feces. The majority of the total administered radioactivity was excreted in feces (83±6.8%) and only a low percentage of the dose recovered in urine (8.1±2.8%). Only less than 2% of what was recovered in humans was unchanged erlotinib, which demonstrates that erlotinib is eliminated predominantly by metabolism. In plasma, unchanged erlotinib represented the major circulating component with the pharmacologically active metabolite M14 accounting for ~5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib include O-demethylation of the side chains followed by oxidation to a carboxylic acid M11 (29.4% of dose), oxidation of the acetylene moiety to a carboxylic acid M6 (21.0%) and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, conjugations of the oxidative metabolites with glucuronic acid (M3, M8 and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.

Key words: anticancer agents, drug disposition, mass spectrometry, metabolite identification

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