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

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 (CL p ) (5.8 1.7 L/h/kg), a large volume of distribution (V ss ) (1.4 0.9 L/kg) and a short half-life (t 1/2 ) (0.4 0.1 h) after a single intravenous administration (5 mg/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 CL p (11.3 8.8 L/h/kg), a high V ss (0.8 1.0 L/kg) and a short t 1/2 (0.070 0.004 h) 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.Key words streptochlorin; 5-hydroxy-2′-isobutyl streptochlorin; pharmacokinetics; metabolism Terrestrial organisms have been a rich source of natural products for drug discovery and development for thousands of years. Since the mid-twentieth century, studies have shown that marine creatures, especially microbes, have provided many bioactive compounds with novel structures. These include compounds such as ziconotide which is an analgesic agent for severe and chronic pain treatment, trabectedin, an anticancer drug, and eribulin for metastatic breast cancer and liposarcoma treatment.

Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

“…The linear calibration range of SP-8356 was (31.25-4000) ng/mL (r 2 > 0.99). The precision and accuracy of the assay were evaluated using quality control samples prepared in triplicate at (30, 300 and 3000) ng/mL as described in previous report [43]. Both the accuracy and precision of this analytical method were within the acceptable ranges [43,44].…”

“…The precision and accuracy of the assay were evaluated using quality control samples prepared in triplicate at (30, 300 and 3000) ng/mL as described in previous report [43]. Both the accuracy and precision of this analytical method were within the acceptable ranges [43,44]. Pharmacokinetic parameters were calculated by noncompartmental analysis using PKSolver [45].…”

Impact of valproic acid on busulfan pharmacokinetics: In vitro assessment of potential drug-drug interaction

“…Although liver S9 sub-cellular fraction is commonly used in drug metabolism assessments, studies demonstrating Bu metabolic stability in this liver fraction are lacking [ 41 , 46 , 61 – 63 ]. In our present work, we started with S9 fraction since it combines both microsomes and cytosolic fractions providing almost complete presentation of liver metabolic profile with entire phase I and phase II enzymes.…”

Synthesis and Biochemical Evaluation of Baicalein Prodrugs

“…Pharmacokinetic studies were conducted with male ICR mice (8 weeks old; 30–35 g body wt.) purchased from Koatech Company (Pyeongtaek, Korea), as reported previously [ 16 ]. Intravenous dosing solutions were prepared in EtOH/20% aqueous HPβCD (10/90 vol%) at 2 and 3 mg/mL for baicalein and compound 2 , respectively.…”