Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects.
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Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P
Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects.
Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15.
- PubMed ID
- 27751676 [ View in PubMed]
- Abstract
PURPOSE: Selumetinib (AZD6244, ARRY-142886), an oral mitogen activated kinase 1/2 inhibitor, is in clinical development for the treatment of a variety of different tumor types. Herein, we report a study that determined the distribution, metabolism, and excretion of selumetinib in healthy male volunteers. METHODS: In this open-label, single-center, Phase I clinical trial, 6 subjects received a single 75-mg dose of [(14)C]-selumetinib. Blood and excreta samples were collected for pharmacokinetic and radiometric analyses. Tolerability monitoring was performed throughout the study. FINDINGS: The Cmax of plasma selumetinib was 1520 ng/mL at 1 hour postdose and declined with a t1/2 of 13.7 hours. Over a 216-hour postdose collection period, total dose recovery was 93% of the radioactive dose, with 59% recovered from feces and 33% from urine. Circulating drug-related material was primarily associated with plasma, with minimal distribution into red blood cells. Selumetinib was the major circulating drug-related component and accounted for 40% of the plasma radioactivity (mean of AUC0-72h pool). The major circulating metabolite (M2; accounting for 22% of the plasma radioactivity) resulted from multiple biotransformation pathways, including loss of the ethanediol moiety in combination with glucuronidation. A further 6 circulating metabolites were identified, each accounting for between 2% and 7% of plasma radioactivity. Selumetinib was a minor component in urine, accounting for
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Selumetinib Cytochrome P450 1A2 Protein Humans NoSubstrateDetails Selumetinib Cytochrome P450 2C8 Protein Humans NoSubstrateDetails Selumetinib Cytochrome P450 2C9 Protein Humans NoSubstrateDetails Selumetinib Cytochrome P450 3A4 Protein Humans NoSubstrateDetails Selumetinib UDP-glucuronosyltransferase 1-3 Protein Humans NoNot Available Details - Drug Reactions
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