Dose-dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti-hepatitis B activity in rats

Baxter Hepburn Kachingwe, Li-Hsuan Wang, Yow-Shieng Uang, Tsurng-Juhn Huang, Shwu-Jiuan Lin

Research output: Contribution to journalArticle

Abstract

Compound 1 (ent-16-oxobeyeran-19-N-methylureido) is a semisynthetic isosteviol derivative that shows anti-hepatitis B virus activity in Huh7 cells by affecting viral DNA transcription and the Toll-like receptor 2/nuclear factor-κB signaling pathway. Thus, the pharmacokinetics and metabolite identification were studied as part of the discovery and development process of compound 1. The pharmacokinetics was evaluated after administration to rats at an intravenous dose of 2 mg/kg, and oral doses of 2, 5 and 10 mg/kg. Plasma concentrations were determined using LC–MS/MS. Moreover, urine samples from rats dosed at 10 mg/kg were scanned for metabolites using UPLC-QTOF-MS/MS. Results for the intravenously administered dose of 2 mg/kg showed that the area under the concentration–time curve was 65,223.31 ± 4269.80 ng min/mL, and the systemic clearance was 0.031 ± 0.0021 L/min. Oral pharmacokinetic parameters were dose-dependent, showing nonproportional increases in the oral AUCs with respective values of 4371.62 ± 3084.81, 22,472.75 ± 9103.33 and 135,141.83 ± 38,934.03 ng min/mL for 2, 5 and 10 mg/kg. The bioavailability was low at 1.5% for 2 mg/kg dose, and at 1.1% for both 5 and 10 mg/kg doses. Metabolites excreted in the urine indicate possible N-oxidation and glucuronide conjugation.

Original languageEnglish
Article numbere4266
Pages (from-to)e4266
JournalBiomedical Chromatography
Volume32
Issue number9
Early online dateApr 24 2018
DOIs
Publication statusPublished - Sep 1 2018

Fingerprint

Pharmacokinetics
Metabolites
Hepatitis B
Rats
Urine
Derivatives
Area Under Curve
Toll-Like Receptor 2
Glucuronides
Viral DNA
Transcription
Viruses
Hepatitis B virus
Biological Availability
Plasmas
Oxidation
isosteviol

Keywords

  • dose-dependency
  • isosteviol derivative
  • metabolite
  • pharmacokinetics
  • urine

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Dose-dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti-hepatitis B activity in rats. / Kachingwe, Baxter Hepburn; Wang, Li-Hsuan; Uang, Yow-Shieng; Huang, Tsurng-Juhn; Lin, Shwu-Jiuan.

In: Biomedical Chromatography, Vol. 32, No. 9, e4266, 01.09.2018, p. e4266.

Research output: Contribution to journalArticle

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