Pharmacokinetics of panaxatrol disuccinate sodium, a novel anti-cancer drug from Panax notoginseng, in healthy volunteers and patients with advanced solid tumors

Abstract

npg IntroductionGinseng has long been known to be multifunctional as both a tonic and a sedative agent. Ginsenosides, the main bioactive components of Ginseng, have become a major focus in cancer research.Based on the properties of different sapogenins, ginsenosides are divided into 3 groups, 20(S)-protopanaxadiol, 20(S)-protopanaxatriol and oleanolic acid glycoside. Many ginsenosides have been found to have anti-cancer activity [1] and are involved in several anti-cancer mechanisms, such as inhibition of cell proliferation [2] , invasion [3] , induction of cell apoptosis [4] and anti-angiogenesis [5] . However, the antitumor mechanism of ginsenoside is not fully clear. Nakata H et al reported that ginsenoside Rh2 inhibited the growth of human ovarian cancer cells cultured in nude mice [6] . Quasipanaxatriol may reverse daunomycin resistance in P388/ADM cells by effectively blocking daunomycin efflux, leading to the accumulation of the drug in the cells [7] . Ginsenoside has been implicated in several signaling pathways, such as MAPK [8] , caspase [9] , NF-kappaB, and JNK pathways [10] . Furthermore, ginsenoside Rg3 ("Shenyi" Capsule) has shown effects on improving body immunity, decreasing toxic effects induced by chemotherapy Aim: To evaluate single-dose and multiple-dose pharmacokinetics of panaxatrol disuccinate sodium in healthy volunteers and patients with advanced solid tumors. Methods: In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m -2 ). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m -2 daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system -Drug and Statistics (DAS) -was applied to assess plasma panaxatrol disuccinate sodium concentration-time data. Results: After a single intravenous dose of 70, 100, or 140 mg·m -2 was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC 0-t , MRT 0-t , VRT 0-t , t 1/2Z , CL z/F , V z/F , and C 0 (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (C max ), trough concentration (C min ), average concentration (C av ), mean steady state AUC (AUC ss ) and the degree of fluctuation were 13.96±15.48 mg·L -1 , 0.18±0.29 mg·L -1 , 0.15±0.29 mg·L -1 , 3.58±6.94 mg·L -1 ·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious. Conclusion: The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m -2 ...

In vitroeffects ofYunnan Baiyaoon canine hemangiosarcoma cell lines

“…However; the average IC 50 for the three cell lines across the three time points (24, 48 and 72 h) was 350.17 µg mL −1 (equal to 350.17 mg L −1 ). This value does exceed the above noted steady state peak concentration and average concentration in plasma but is in a similar range with the mean steady state concentration achieved in plasma . On the basis of dosing of other chemotherapeutic medications in veterinary medicine and the results of this in vitro study, this would appear to be a clinically attainable dose in the canine patient.…”

“…This value does exceed the above noted steady state peak concentration and average concentration in plasma but is in a similar range with the mean steady state concentration achieved in plasma. 43 On the basis of dosing of other chemotherapeutic medications in veterinary medicine and the results of this in vitro study, this would appear to be a clinically attainable dose in the canine patient. It should also be noted that the IC 50 data presented here is based on the entire Yunnan Baiyao compound and separation of the individual ingredients is more likely to result in even more comparable data.…”

“…The steady‐state peak concentration, average concentration and mean steady state AUC in plasma were 13.96±15.48, 0.15±0.29 and 148.00±117.18 mg L −1 , respectively. An intravenous injection at a dose of 100 mg m −2 has been suggested for further phase II clinical trials . We can not necessarily correlate what is achievable in vitro to in vivo availability based upon our study as we are not examining an individual component of Yunnan Baiyao .…”

“…An intravenous injection at a dose of 100 mg m −2 has been suggested for further phase II clinical trials. 43 We can not necessarily correlate what is achievable in vitro to in vivo availability based upon our study as we are not examining an individual component of Yunnan Baiyao. However; the average IC 50 for the three cell lines across the three time points (24, 48 and 72 h) was 350.17 μg mL −1 (equal to 350.17 mg L −1 ).…”

Therapeutic impacts of Indian and Korean ginseng on human beings – a review

“…As colon tumors have been shown to highly express COX-2 protein, and given, that many NSAID drugs also suppress COX-1, it is tempting to speculate that herbal products that inhibit one or both forms of the COX enzyme will be effective agents for the prevention of cancer in man (Wargovich, 2001 (Yan et al, 2010). As colon tumors have been shown to highly express COX-2 protein, and given, that many NSAID drugs also suppress COX-1, it is tempting to speculate that herbal products that inhibit one or both forms of the COX enzyme will be effective agents for the prevention of cancer in man (Wargovich, 2001 (Yan et al, 2010).…”