Abstract
An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h−1 for IQ and 1.7 h−1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability.
Highlights
Ilimaquinone (IQ) is isolated from Hippiospongia metachromia [1], which is a marine sponge.This substance exhibits several pharmacological effects, including antiviral action against human immune-sufficient virus [2], antibacterial properties against Staphylococcus aureus [3], anti-cancer activity for various types of cancer cells [4,5,6,7,8], and inhibitory activity against nitrogen oxide (NO)production in lipopolysaccharide-stimulated in BV2 microglia cells [9].In nature, the substance mainly exists as a mixture of epimers, IQ, and epi-ilimaquinone, at a ratio of 2:1 (Figure 1)
Both IQ and epi-IQ were accurately and precisely determined in rat plasma using a single method for the first time
The method has been successfully used to characterize the stereo-selective pharmacokinetics of IQ and epi-IQ in rats
Summary
Ilimaquinone (IQ) is isolated from Hippiospongia metachromia [1], which is a marine sponge. The substance mainly exists as a mixture of epimers, IQ, and epi-ilimaquinone (epi-IQ), at a ratio of 2:1 (Figure 1). Both isomers have revealed to contribute to decreasing the level of β-catenin, which suppresses the Wnt/β-catenin pathway [6]. A recent report described a novel analytical method for determining IQ in rat plasma using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). It was used in a pharmacokinetic study following per oral (p.o.) administration of IQ [10]. Individual epimers were separately given orally to clarify the drug-drug interactions between the epimers and to monitor the epimeric biotransformation in vivo
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