Species differences in metabolism of a new antiepileptic drug candidate, DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide]

Masahiro Yahata, Yuji Ishii, Tetsuya Nakagawa, Takao Watanabe, Kiyoko Bando

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The metabolism and pharmacokinetics of DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide], an antiepileptic drug candidate, was investigated in rats, dogs, and humans. In human hepatocytes, [14C]DSP-0565 was primarily metabolized via amide bond hydrolysis to (2′-fluoro[1,1′-biphenyl]-2-yl)acetic acid (M8), while in rat and dog hepatocytes, it was primarily metabolized via both hydrolysis to M8 and hydroxylation at the benzene ring or the benzyl site to oxidized metabolites. After single oral administration of [14C]DSP-0565 to rats and dogs, the major radioactivity fraction was recovered in the urine (71–72% of dose) with a much smaller fraction recovered in feces (23–25% of dose). As primary metabolites in their excreta, M8, oxidized metabolites, and glucuronide of DSP-0565 were detected. The contribution of metabolic pathways was estimated from metabolite profiles in their excreta: the major metabolic pathway was oxidation (57–62%) and the next highest was the hydrolysis pathway (23–33%). These results suggest that there are marked species differences in the metabolic pathways of DSP-0565 between humans and animals. Finally, DSP-0565 human oral clearance (CL/F) was predicted using in vitro–in vivo extrapolation (IVIVE) with/without animal scaling factors (SF, in vivo intrinsic clearance/in vitro intrinsic clearance). The SF improved the underestimation of IVIVE (fold error = 0.22), but the prediction was overestimated (fold error = 2.4–3.3). In contrast, the use of SF for hydrolysis pathway was the most accurate for the prediction (fold error = 1.0–1.4). Our findings suggest that understanding of species differences in metabolic pathways between humans and animals is important for predicting human metabolic clearance when using animal SF.

Original languageEnglish
Pages (from-to)165-175
Number of pages11
JournalBiopharmaceutics and Drug Disposition
Volume40
Issue number5-6
DOIs
Publication statusPublished - May 1 2019

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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