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Identification of a Discrete Diglucuronide of GDC-0810 in Human Plasma after Oral Administration.
Zhang, Chenghong; Su, Dian; Choo, Edna F; Liu, Lichuan; Bobba, Sudheer; Jorski, Jamie D; Ho, Quynh; Wang, Jing; Kenny, Jane R; Khojasteh, S Cyrus; Zhang, Donglu.
Afiliação
  • Zhang C; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Su D; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Choo EF; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Liu L; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Bobba S; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Jorski JD; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Ho Q; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Wang J; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Kenny JR; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Khojasteh SC; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
  • Zhang D; Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California (E.F.C., S.B., J.D.J., J.W., J.R.K., S.C.K., D.Z.); Pfizer, South San Francisco, California (C.Z.); Bicycle Therapeutics, Cambridge, Massachusetts (D.S.); Innovative Research BU, Yifan Pharmaceutical,
Drug Metab Dispos ; 51(10): 1284-1294, 2023 10.
Article em En | MEDLINE | ID: mdl-37349116
ABSTRACT
GDC-0810 is a small molecule therapeutic agent having potential to treat breast cancer. In plasma of the first-in-human study, metabolite M2, accounting for 20.7% of total drug-related materials, was identified as a discrete diglucuronide that was absent in rats. Acyl glucuronide M6 and N-glucuronide M4 were also identified as prominent metabolites in human plasma. Several in vitro studies were conducted in incubations of [14C]GDC-0810, synthetic M6 and M4 with liver microsomes, intestinal microsomes, and hepatocytes of different species as well as recombinant UDP-glucuronosyltransferase (UGT) enzymes to further understand the formation of M2. The results suggested that 1) M2 was more efficiently formed from M6 than from M4, and 2) acyl glucuronidation was mainly catalyzed by UGT1A8/7/1 that is highly expressed in the intestines whereas N-glucuronidation was mainly catalyzed by UGT1A4 that is expressed in the human liver. This complicated mechanism presented challenges in predicting M2 formation using human in vitro systems. The absence of M2 and M4 in rats can be explained by low to no expression of UGT1A4 in rodents. M2 could be the first discrete diglucuronide that was formed from both acyl- and N-glucuronidation on a molecule identified in human plasma. SIGNIFICANCE STATEMENT A discrete diglucuronidation metabolite of GDC-0810, a breast cancer drug candidate, was characterized as a unique circulating metabolite in humans that was not observed in rats or little formed in human in vitro system.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Glucuronídeos Tipo de estudo: Diagnostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Glucuronídeos Tipo de estudo: Diagnostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article