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Elimination of tucatinib, a small molecule kinase inhibitor of HER2, is primarily governed by CYP2C8 enantioselective oxidation of gem-dimethyl.
Sun, Hao; Cardinal, Kristen A; Wienkers, Larry; Chin, Alice; Kumar, Vineet; Neace, Calvin; Henderson, Clark; Endres, Christopher J; Topletz-Erickson, Ariel; Regal, Kelly; Vo, Alex; Alley, Stephen C; Lee, Anthony J.
Afiliación
  • Sun H; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA. hsun@seagen.com.
  • Cardinal KA; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Wienkers L; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Chin A; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Kumar V; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Neace C; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Henderson C; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Endres CJ; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Topletz-Erickson A; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Regal K; Array Biopharma, Boulder, CO, USA.
  • Vo A; ProPharma Services, Superior, CO, USA.
  • Alley SC; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
  • Lee AJ; Seagen Inc, 21823 30th Dr SE, Bothell, WA, 98021, USA.
Cancer Chemother Pharmacol ; 89(6): 737-750, 2022 06.
Article en En | MEDLINE | ID: mdl-35435471
PURPOSE: Tucatinib, a small molecule for the treatment of metastatic HER2-positive breast cancer, was extensively metabolized in humans to multiple oxidative metabolites. To fully understand the elimination and biotransformation pathways of tucatinib, we investigated the in vitro and in vivo metabolism of tucatinib, and also conducted a Phase I trial using [14C]tucatinib. METHODS: To identify the responsible enzymes for tucatinib clearance, we investigated the in vitro metabolism of tucatinib including enzyme phenotyping, which facilitated the discovery of several metabolites in human and monkey plasma and excreta, in particular M1 (ONT-993, an aliphatic hydroxylated metabolite). Stereoselective formation of M1 was further investigated in vitro, in vivo, and in silico. RESULTS: In humans, approximately 86% of the total radiolabeled dose was recovered in feces and 4% in urine; in plasma, approximately 76% of radioactivity circulated as parent drug, with 19% attributed to multiple metabolites. The primary isoforms responsible for the elimination of tucatinib were CYP2C8 and CYP3A4/5. CYP2C8 was shown to possess sole catalytic activity for the formation of M1, whereas CYP3A4/5 and aldehyde oxidase catalyzed the formation of the remaining metabolites. Subsequent investigation revealed that M1 was formed in a stereoselective manner. Examination of the enantiomeric ratio of M1 stereoisomers observed in humans relative to cynomolgus monkeys revealed comparable results, suggesting that the enantiomers that comprise M1 were not considered to be unique or disproportionately high in human. CONCLUSION: CYP2C8 and CYP3A4/5 are the primary drug-metabolizing enzymes involved in the in vitro metabolism of tucatinib, which provided the basis to describe human disposition of tucatinib and formation of the observed metabolites.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Citocromo P-450 CYP3A / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Chemother Pharmacol Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Citocromo P-450 CYP3A / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Chemother Pharmacol Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania