Dose-dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti-hepatitis B activity in rats.
Baxter Hepburn KachingweLi-Hsuan WangYow-Shieng UangTsurng-Juhn HuangShwu-Jiuan LinPublished in: Biomedical chromatography : BMC (2018)
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.
Keyphrases
- ms ms
- toll like receptor
- nuclear factor
- hepatitis b virus
- signaling pathway
- inflammatory response
- induced apoptosis
- immune response
- small molecule
- sars cov
- transcription factor
- high dose
- high throughput
- pi k akt
- cell cycle arrest
- cell proliferation
- cell death
- bioinformatics analysis
- high resolution
- oxidative stress
- low dose
- nucleic acid