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

Fingerprint

Anticonvulsants
Metabolic Networks and Pathways
Hydrolysis
Dogs
Hepatocytes
Glucuronides
Hydroxylation
Benzene
Feces
Amides
Acetic Acid
Radioactivity
Oral Administration
acetamide
diphenyl
Pharmacokinetics
Urine

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

Species differences in metabolism of a new antiepileptic drug candidate, DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide]. / Yahata, Masahiro; Ishii, Yuji; Nakagawa, Tetsuya; Watanabe, Takao; Bando, Kiyoko.

In: Biopharmaceutics and Drug Disposition, Vol. 40, No. 5-6, 01.05.2019, p. 165-175.

Research output: Contribution to journalArticle

@article{8e95d3ba730f4a66ac6a68823b4c982e,
title = "Species differences in metabolism of a new antiepileptic drug candidate, DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide]",
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.",
author = "Masahiro Yahata and Yuji Ishii and Tetsuya Nakagawa and Takao Watanabe and Kiyoko Bando",
year = "2019",
month = "5",
day = "1",
doi = "10.1002/bdd.2180",
language = "English",
volume = "40",
pages = "165--175",
journal = "Biopharmaceutics and Drug Disposition",
issn = "0142-2782",
publisher = "John Wiley and Sons Ltd",
number = "5-6",

}

TY - JOUR

T1 - Species differences in metabolism of a new antiepileptic drug candidate, DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide]

AU - Yahata, Masahiro

AU - Ishii, Yuji

AU - Nakagawa, Tetsuya

AU - Watanabe, Takao

AU - Bando, Kiyoko

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065642745&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065642745&partnerID=8YFLogxK

U2 - 10.1002/bdd.2180

DO - 10.1002/bdd.2180

M3 - Article

VL - 40

SP - 165

EP - 175

JO - Biopharmaceutics and Drug Disposition

JF - Biopharmaceutics and Drug Disposition

SN - 0142-2782

IS - 5-6

ER -