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To provide insights into the mechanism for the attenuate-synergistic effect of Zuota to Tibetan medicine Renqing Mangjue, a contrasted study was carried out on the pharmacokinetics of brucine and strychnine in mice plasm, which are active and toxicant ingredient in the Tibetan medicine Renqing Mangjue. LC-MS/MS was used to detect simultaneously the concentrations of brucine and strychnine in mice plasm at-different time intervals after administration parallelly and randomly, and the pharmacokinetic software Kinetica 5. 0 was selected to non-compartmental analysis (NCA) for data, and statistical analysis software SPSS 19. 0 was used for significance test on the pharmacokinetic parameters. A reliable LC-MS/MS method was established for the determination of brucine and strychnine in blood plasma, which are consistent with the requirements of the preclinical pharmacokinetic study confirmed by the methodology. The linear concentration ranges of brucine and strychnine were 0.301-104.4 µg · L(-1) (r = 0.999 5) and 0.305-106 µg · L(-1) (r = 0.999 7), respectively; The intra-day and inter-day variable coefficients were both less than 10.0% with good precision; The average extraction recoveries of brucine and strychnine were 116.23% and 112.82%, and RSD were 3.2% and 2.3% separately;The average matrix effects of brucine and strychnine were 122.48% and 116.36%, and RSD were 7.7% and 4.4%, respectively. The pharmacokinetic results showed that AUCtot of brucine and strychnine in Zuota group were both increased remarkably (P < 0.05), and the Cmax of brucine in Zuota group was about 5.25-fold higher than that of brucine in non-Zuota group (P < 0.05). The Tmax of brucine and strychnine reduced to one-eighth and one-quarter respectively compared with those in Non-Zuota group. In addition, the eliminations of brucine and strychnine in vivo were accelerated after the compatibility of Zuota. A significant difference (P < 0.05) occurred at the MRT0-t, of brucine, while the MRT0-∞ and Lz of strychnine were statistically significant upon the inspection level α = 0.1. It was found that the absorption degree of brucine and strychnine in Zuota group increased in the range of the safe dose (or concentration), while their elimination rates were accelerated, which may be one of the mechanisms for attenuate-synergistic effect of Zuota to Tibetan medicine Renqing Mangjue.

Zuotais regarded as the king of Tibetan medicine. However, the major starting material ofZuotais mercury, which is one very toxic heavy metal. This has aroused serious doubts on the biosafety ofZuotacontaining drugs. In this study, we quantified the Hg contents in fourZuotasamples, monitored the release of Hg in simulated gastric/intestinal juice and evaluated their cytotoxicity to Caco-2 cells. Our results showed that the Hg contents inZuotasamples were in the range of 566–676 mg/g. Fortunately, the release of Hg fromZuotasamples was very low in simulated gastric juice, and much lower in simulated intestinal juice. Direct contact ofZuotawith Caco-2 cells led to dose-dependent cytotoxicity, including activity loss and membrane leakage. The toxicity was closely related to apoptosis, because the caspase 3/7 levels of Caco-2 cells increased after the exposure toZuota. Interestingly,Zuotasamples inhibited the oxidative stress at low concentrations, but the toxicity could be relived by antioxidants. The possible toxicity should be attributed to the cellular uptake ofZuotaparticulates. Beyond the cytotoxicity, significant differences amongZuotasamples from different institutions were observed, suggesting that the preparation process ofZuotahad meaningful influence of its biosafety. The implications to the safety and clinical applications ofZuotaare discussed. [ABSTRACT FROM AUTHOR]