Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity

Abstract

Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic ß-cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25–200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications.

Waste to Medicine: Evidence from Computational Studies on the Modulatory Role of Corn Silk on the Therapeutic Targets Implicated in Type 2 Diabetes Mellitus

“…The association of many of the CS compounds to cAMP targets such as ADORA1, HCAR2, and GABBR1 highlighted them among the genes in the cAMP pathway. Adenosine A1 receptor (ADORA1), a G protein-coupled receptor, inhibits the enzyme adenylate cyclase and plays a role in the regulation of cell metabolism and gene transcription, and therefore, has been identified as an important drug target for the treatment of various diseases and illnesses [75,76], including T2DM via glucose homeostasis and glucagon secretion regulation [77]. The identification of ADORA1 as a key target for T2DM and related complications (e.g., nephropathy) therapy buttresses previous studies (on morusin, kuwanon C, and morusyunnansin) from Morus alba (leaves) and Salvia miltiorhiza through NP and molecular docking analyses [77,78].…”

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

“…Troxerutin also induced oxidative stress by elevating malondialdehyde concentration while reducing the activity levels of glutathione peroxidase and superoxide dismutase [140]. The anticancer properties of icariin have been documented in the literature [141][142][143][144][145][146]. The anticancer properties of icariin against human HeLa cervical cancer cell line and normal HCvEpC cells were assessed previously [146].…”

Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice

“…It was also demonstrated that SZ-As protected mice from HFD-mediated hepatic steatosis, triglyceride accumulation and adipose tissue inflammation, while the anti-inflammatory role appeared to depend on the blockage of p38 MAPK, ERK and JNK signaling pathway activation in macrophages [ 11 , 12 ]. Notably, tissue distribution analysis suggested that after oral administration, the major constituents of SZ-As are observed predominantly in the liver, followed by the adipose tissues [ 13 ], which revealed the potential regulating effects of SZ-As on liver and adipose tissue. So far, there are relatively few reports of the role of SZ-As in treating liver lipid metabolism disorder, and their therapeutic mechanism also remains unclear.…”