Pharmacokinetics and tissue distribution of five bufadienolides from the Shexiang Baoxin pill following oral administration to mice

Zhang

Fundamemntal Clinical Pharma

et al. 2017

In this study, we investigated the effect of bufalin on the human ether-à-go-go-related gene (hERG) K channels using the perforated patch recording technique. We measured a half-maximal inhibitory concentration (IC ) of 24.83 μM and maximal inhibitory effect of 39.45 ± 1.14% with bufalin. These findings suggest that bufalin is a potent hERG K channel blocker and may provide a new way for understanding Chan Su-induced arrhythmia.

Section: Discussionsupporting

confidence: 71%

Bufalin, a bufanolide steroid from the parotoid glands of the Chinese toad, suppresses hERG K⁺ currents expressed in HEK293 cells

Zhang

Fundamemntal Clinical Pharma

et al. 2017

“…The AUC 0–t of double peaks suggested that enterohepatic recirculation might have occurred 25. The double-peak phenomenon reported here was in agreement with previous reports 26. Previous pharmacokinetic research presented an analogous phenomenon in rats 27.…”

Section: Discussionsupporting

confidence: 93%

Radiosynthesis and pharmacokinetics of [<sup>18</sup>F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

Yang¹,

Liu²,

Huang³

et al. 2017

OTT

PurposeBufalin, the main component of a Chinese traditional medicine chansu, shows convincing anticancer effects in a lot of tumor cell lines. However, its in vivo behavior is still unclear. This research aimed to evaluate how bufalin was dynamically absorbed after intravenous injection in animal models. We developed a radiosynthesis method of [18F]fluoroethyl bufalin to noninvasively evaluate the tissue biodistribution and pharmacokinetics in hepatocellular carcinoma-bearing mice.Methods[18F]fluoroethyl bufalin was synthesized with conjugation of 18F-CH2CH2OTs and bufalin. The radiochemical purity was proved by the radio-high-performance liquid chromatography (HPLC). The pharmacokinetic studies of [18F]fluoroethyl bufalin were then performed in Institute of Cancer Research (ICR) mice. Furthermore, the biodistribution and metabolism of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing nude mice were studied in vivo by micro-positron emission tomography (micro-PET).ResultsThe radiochemical purity (RCP) of [18F]fluoroethyl bufalin confirmed by radio-HPLC was 99%±0.18%, and [18F]fluoroethyl bufalin showed good in vitro and in vivo stabilities. Blood dynamics of [18F]fluoroethyl bufalin conformed to the two compartments in the ICR mice model. The pharmacokinetic parameters of [18F]fluoroethyl bufalin were calculated by DAS 2.0 software. The area under concentration–time curve (AUC0–t) and the values of clearance (CL) were 540.137 μg/L·min and 0.001 L/min/kg, respectively. The half-life of distribution (t1/2α) and half-life of elimination (t1/2β) were 0.693 and 510.223 min, respectively. Micro-PET imaging showed that [18F]fluoroethyl bufalin was quickly distributed via the blood circulation; the major tissue biodistribution of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing mice was liver and bladder.Conclusion[18F]fluoroethyl bufalin was accumulated rapidly in the liver at an early time point (5 min) post injection (pi) and then declined slowly, mainly through both the hepatic pathway and the renal pathway. Our study showed the biodistribution of [18F]fluoroethyl bufalin in micro-PET images and provided visible information for demonstrating the bioactivities of bufalin.

“…Previous studies have demonstrated that the major pharmacological constituents derived from toad skins are hydrosoluble indole alkaloids (bufotenine, bufotenidine, and cinobufotenine) and liposoluble steroidal cardiac glycosides mainly composed of bufadienolides 3,4. Bufadienolide-type cardiotonic steroids are a class of C-24 steroids with a characteristic pyrone ring at C-17 and have been identified as major active components and marker compounds of venenum bufonis 5. Currently, bufadienolides, including bufotalin, bufalin, and resibufogenin, have been found to show potent cytotoxic and growth inhibitory activity against various human cancer cells 6–15.…”

Section: Introductionmentioning

confidence: 99%

Arenobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo

Lv¹,

Lin²,

Peng³

et al. 2017

OTT

Esophageal squamous cell carcinoma (ESCC) is often diagnosed at late incurable stage and lacks effective treatment strategy. Bufadienolides are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor with novel anticancer activity. However, there is little information about the effects and action mechanisms of bufadienolides on ESCC cells. In this study, the in vitro and in vivo anti-ESCC activities of bufadienolides, including bufalin (Bu) and arenobufagin (ArBu), were examined and the underlying molecular mechanisms were elucidated. The results showed that ArBu exhibited higher anticancer efficacy than Bu against a panel of five ESCC cells, with IC50 values ranging from 0.8 μM to 3.6 μM. However, ArBu showed lower toxicity toward Het-1A human normal esophageal squamous cells, indicating its great selectivity between cancer and normal cells. Moreover, ArBu effectively induced ESCC cell apoptosis mainly by triggering caspase activation through intrinsic and extrinsic pathways. Treatment of ESCC cells also significantly activated p53 signaling by enhancing its phosphorylation. Interestingly, transfection of cells with p53 small interfering RNA significantly inhibited the ArBu-induced p53 phosphorylation and the overall apoptotic cell death. Furthermore, ArBu also demonstrated novel in vivo anticancer efficacy by inhibiting the tumor growth through activation of p53 pathway. Taken together, these results demonstrate the p53-targeting therapeutic potential of bufadienolides against ESCC.