Pharmacokinetic, Tissue Distribution, Metabolite, and Toxicity Evaluation of the Matrine Derivative, (6aS, 10S, 11aR, 11bR, 11cS)-10-Methylaminododecahydro-3a, 7a-Diaza-benzo (de) Anthracene-8-thione

Abstract

MASM, a structurally modified derivative of matrine, exhibits superior efficacy in reducing inflammation and liver injury in rats when compared to matrine. This study aims to investigate the pharmacokinetic profile and acute toxicity of MASM. Pharmacokinetic results revealed that MASM exhibited rapid absorption, with a Tmax ranging from 0.21 ± 0.04 h to 1.31 ± 0.53 h, and was eliminated slowly, with a t1/2 of approximately 10 h regardless of the route of administration (intravenous, intraperitoneal, or intragastric). The absolute intragastric bioavailability of MASM in rats was determined to be 44.50%, which was significantly higher than that of matrine (18.5%). MASM was detected in all rat tissues including the brain, and through the utilization of stable isotope-labeled compounds and standard references, ten metabolites of MASM, namely sophocarpine, oxysophocarpine, and oxymatrine, were tentatively identified. The LD50 of MASM in mice was determined to be 94.25 mg/kg, surpassing that of matrine (83.21 mg/kg) based on acute toxicity results. Histopathological and biochemical analysis indicated no significant alterations in the primary organs of the low- to medium-dosage groups of MASM. These findings provide valuable insights into the efficacy and toxicity profile of MASM.

Keywords

• MASM
• pharmacokinetics
• tissue distribution
• metabolites
• toxicity evaluation