異甜菊醇衍生物NC-8之藥物動力學

Pharmacokinetics of an isosteviol derivative NC-8

巴克斯

異甜菊醇衍生物NC-8之藥物動力學 ； Pharmacokinetics ； isosteviol-derivative ； NC-8

臺北醫學大學藥學系(碩博士班)學位論文

2018年

博士

林淑娟

英文

異甜菊醇衍生物NC-8之藥物動力學

NC-8 (ent-16-oxobeyeran-19-N-methylureido) is a semi-synthetic isosteviol derivative that has shown anti-hepatitis B virus activity in Huh7 cells affecting viral DNA transcription, viral gene expression and the TLR2/NF-B signaling pathway. Thus, this study of the pharmacokinetics and metabolite identification was done as a part of development of NC-8. NC-8 was synthesized from isosteviol to get quantity sufficient for animal study, with satisfactory purity. The synthesized NC-8 is with ≥ 97 % purity. A bioanalytical method for the analysis of NC-8 in rat plasma was developed and validated. The pharmacokinetics of NC-8 was evaluated after administration at intravenous dose of 2 mg/kg, and oral doses of 2, 5 and 10 mg/kg in rats. Plasma concentrations were determined using LC-MS/MS and while urine samples from rats dosed at 10 mg/kg were scanned for metabolites using UPLC-QTOF-MS/MS. Method development and validation resulted in a lower limit of quantitation of 0.5 ng/ml. The linear scope of the standard curve was between 0.5 and 500 ng/ml (r2 = 0.9967). Both the precision (coefficient of variation; %) and accuracy (relative error; %) were within acceptable criteria of < 15 %. Recoveries ranged from 104 % to 113.4 %, and the matrix effects (absolute) were non-significant (CV ≤ 6 %). The validated method was successfully applied to investigate the pharmacokinetics of NC-8 in male Sprague-Dawley rats. The results for intravenously administered 2 mg/kg dose showed that the area under the concentration-time curve (AUC), the half-life (t1/2), steady state volume of distribution (Vss) and the systemic clearance (Cl) were 65,223.31 ± 4,269.79 ng/ml.min, 35.46 ± 7.94 min, 0.63 ± 0.032 L and 0.031 ± 0.0021 L/min, respectively. After oral administration, the pharmacokinetic parameters showed dose dependent increase. Increases in dose produced non-proportional increases in oral AUCs with values of 4,371.62 ± 3,084.81, 22,472.75 ± 9,103.33 and 135,141.83 ± 38,934.03 ng/ml.min for 2, 5 and 10 mg/kg, respectively. The clearance decreased with increase in oral dose. The bioavailability was low at approximately 1% for 2, 5 and 10 mg/kg oral doses. Oxidized and glucuronide conjugated urine metabolites of NC-8 were postulated. The method developed and validated provided an analytical means to better understand the preliminary pharmacokinetics of NC-8 for investigations on further drug development. The results showed dose-dependent pharmacokinetics of NC-8 and this could be due to saturable intestinal and hepatic first-pass effect. The metabolites excreted in urine indicate possible N-oxidation and glucuronide conjugation as part of metabolic pathways.

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