Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2 '-isobutyl Streptochlorin, in Mice SCIE SCOPUS

Cited 3 time in WEB OF SCIENCE Cited 3 time in Scopus
Title
Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2 '-isobutyl Streptochlorin, in Mice
Author(s)
Zhou, Yuanyuan; Choi, Yeon Jung; Kim, Eunyeong; Oh, Mun Hwan; Shin, Hee Jae; Kim, Sang Kyum; Lee, Kiho
KIOST Author(s)
Shin, Hee Jae(신희재)
Publication Year
2018-03
Abstract
The purpose of this study was to investigate the pharmacokinetics and metabolism of streptochlorin and its derivative 5-hydroxy-2'-isobutyl streptochlorin (HIS) in mice. Plasma concentration of streptochlorin declined rapidly resulting in a high sustemic plasma clearance (CLp) (5.8 +/- 1.7L/h/kg), a large volume of distribution (V-ss) (1.4 +/- 0.9L/kg) and a short half-life (t(1/2)) (0.4 +/- 0.1 h) after a single intravenous administration (5mg/kg). Oral bioavailability (F) was 10.3 +/- 3.4% after a single oral administration (10 mg/kg). HIS also showed a rapid plasma decline with a high CLp (11.3 +/- 8.8L/h/kg), a high V-ss (0.8 +/- 1.0L/kg) and a short t(1/2) (0.070 +/- 0.004h) following intravenous administration. It was not detected in plasma after oral administration. Metabolic stability studies using mouse liver microsomes and S9 fractions predicted a high hepatic clearance for both compounds, consistent with the in vivo data. Metabolite identification studies revealed three metabolic pathways for streptochlorin: monooxygenation, glucuronidation of the indole moiety and oxidative opening of the 4-chlorooxazole ring. HIS was metabolized via monooxygenation of the isobutyl chain and glucuronidation of the indole ring. These results may aid in structural optimization to mitigate the metabolic liability of streptochlorin.
ISSN
0918-6158
URI
https://sciwatch.kiost.ac.kr/handle/2020.kiost/1001
Bibliographic Citation
BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.41, no.3, pp.326 - 337, 2018
Publisher
PHARMACEUTICAL SOC JAPAN
Subject
MARINE NATURAL-PRODUCTS; IN-VITRO METABOLISM; WELL-STIRRED MODEL; DRUG DISCOVERY; ALDEHYDE OXIDASE; RAT; PERMEABILITY; PARAMETERS; CLEARANCE; ANALOGS
Keywords
streptochlorin; 5-hydroxy-2 ' -isobutyl streptochlorin; pharmacokinetics; metabolism
Type
Article
Language
English
Document Type
Article
Publisher
PHARMACEUTICAL SOC JAPAN
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