Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus.

Sesterterpene MHO7 derived from mangrove fungus is a novel estrogen receptor degrader for the treatment of breast cancer. To explore its safety and pharmacokinetics in vivo, Log P/D values, stability in simulated gastric/intestinal (SGF/SIF), toxicity, and pharmacokinetics studies were carried mainly by liquid chromatography technique coupled with tandem mass spectrometry (LC-MS/MS) method in mice, and the effect of MHO7 on mice gut microbiota at different time points was revealed by 16S rRNA sequencing. Log P/D values ranged 0.93-2.48, and the compound in SGF and SIF is stable under the concentration of 5 mM·L(-)(1). The maximum tolerance dose (MTD) of oral administration in mice was 2400 mg·kg(-)(1). The main pharmacokinetics parameters were as following: C(max) of 1.38 μg·mL(-)(1), T(max) of 8 h, a half-life (t(1/2)) of 6.97 h, an apparent volume of mean residual time (MRT) of 8.76 h, and an area under the curve (AUC) of 10.50 h·μg·mL(-)(1). MHO7 displayed a wide tissue distribution in mice, with most of the compound in liver (3.01 ± 1.53 μg·g(-)(1)) at 1 h, then in fat (5.20 ± 3.47 μg·g(-)(1)) at 4 h, and followed by reproductive organs with the concentrations of 23.90 ± 11.33 μg·g(-)(1),13.69 ± 10.29 μg·g(-)(1), 1.46 ± 1.23 μg·g(-)(1), and 0.36 ± 0.46 μg·g(-)(1) at 8, 12, 20 and 30 h, respectively. The most influenced genera of gut microbiome belonged to phylum Firmicutes (21 of 28), among which 18 genera originated from the order Clostridiales, class Clostridia, and families of Ruminococcaceae (11 of 18) and Lachnospiraceae (4 of 18). These results provide that MHO7 is suitable for oral administration in the treatment of breast cancer with the target organs of reproductive organs and regulation on Ruminococcaceae and Lachnospiraceae.