| Objective The purpose of this study was to investigate the pharmacokinetics and metabolites of tetrandrine (Tet) in rabbits and rats, and its anti-tumor properties in order to evaluate the reasonableness for the treatment of Tet in neoplastic diseases.Methods A simple RP-HPLC method was used to determine the concentration of Tet in plasma, urine and faeces after rabbits or SD rats were given certain amount of Tet by intravenous or oral route. The pharmacokinetic parameters were calculated with the DAS software. The effects of Tet alone or in combination of other anticancer drugs on Hep3b hepatic carcinoma cell, K562 leukemia cell, MG63 osteogenic sarcoma cell, and SKOV3 ovarian cancer were investigated by means of morphology, MTT assay, flow cytometry, Western-blot and other methods and techniques.Results1. It was shown that the blood concentration-time data of Tet fit the classical two-compartment model, no matter the drug was administered intravenously or orally. The values of Cmax, AUC0→∞, clearance (Cl0→∞), volume of distribution (Vd), and elimination half-life (t1/2β) of Tet were 388.81±160.04 ng/mL, 59861.149±26962.196μg/L*min, 0.503±0.173 L/min/kg,179±76.185 L/kg,and 283.808±162.937 min for intravenous injection of 5.0 mg/kg,and 92.448±23.795 ng/mL, 18986.217±7462.308μg/L*min,0.805±0.267 L/min/kg,110.284±94.176 L/kg,and 732.919±847.32 min for gavage administration of 10 mg/kg ,respectively. The results indicate that Tet displays a limited absorption in intestinal tract, even though it has a favorable pharmacokinetic profile after oral or intravenous administration.2. 23.4% and 23.1% of total dose were excreated from urine and feces, respectively,in 120 h after three consecutive dose of Tet was given intravenously to rabbits;the former contained 4.05% of prodrug and later was 7.81%,and both of urine and feces contained 3 metabolites of Tet. On the contrary, 65.1% and 24.1% of total dose were excreated by urine and feces with 14.2% and 7.0% of prodrug,respectively, in 70 h after rats were given orally. Besides,two metabolites in urine and three metabolites in feces were found when Tet was given to rats.3. Hep3b/5-Fu , K562/ADM , MG63/cDDP , and SKOV3/cDDP resistant strains were established. It was found that the basic expressions of P-gp and MRP1 proteins were lower in Hep3b/5-Fu and K562/ADM than in their parent strains. Tet(0.33-1.0μg/mL)showed dualistic modulation for expressions of resistance-related proteins from different tumor cells: 0.33μg/mL of Tet up-regulated expression of P-gp in Hep3b,Hep3b/5-Fu,K562, and K562/ADM,it also up-regulated expression of MRP1 in K562 and K562/ADM;0.5μg/mL of Tet down-regulated MRP1 expression in K562 and K562/ADM;1.0μg/mL of Tet up-regulated MRP1 expression of Hep3b/5-Fu. There was no difference of basic LRP expression in both parent and resistant strains of Hep3b and K562 and Tet did not affect its expression.1. Effects of Tet on cell growth curves,cell cycles,cell survaval rates,as well as IC50 of ADM,5-Fu and cDDP inhibiting both parent and resistant strains were investigated. It was found that 0.33μg/mL Tet promoted exponentially growing cells into programmed death without influence on cell cycles;0.33-1.0μg/mL Tet had a weak inhibitive effects on four parent cells above, but had no effects on resistant cells,even increased their survaval rates. A dualistic effects of Tet on IC50 of ADM,5-Fu,and cDDP inhibiting tumor cells was observed:0.33μg/mL obviously elevated IC50 of ADM and cDDP acting on K562,cDDP acting on Hep3b/5-Fu and MG63/cDDP,and cDDP and 5-Fu acting on SKOV3;0.5μg/mL significantly decreased IC50 of cDDP inhibiting K562,Hep3b/5-Fu and MG63/cDDP;1.0μg/mL clearly diminished Ic50 of 5-Fu acting on Hep3b/5-Fu and SKOV3.Conclusion1. The characteristics of Tet pharmacokinetics fit two-compartment model after it is given intravenously or orally to rabbits. Tet has a poor absorption in intestinal tract with slow excreation.2. Slow metabolism of Tet with three metabolites in rabbits and rats is observed. The main route of Tet elimination is metabolized in body. The main excreation routes of Tet are urine and bile in rabbits. Slower metabolism and excreation of Tet are observed in rabbits than in rats.3. There is no obvious relation between resistance of Hep3b/5-Fu and K562/ADM and LRP expression.4. Safe concentration of Tet that can be obtained has a weak inhibitive effects on tumor cells. Tet shows a dualistic effect on parent and resistant strains when it is used in combination of other antitumor drugs:low concentration induces development of cell resistance , and high concentration shows reversing resistance of tumor cells.1. It is considerable to weigh advantage of Tet against its disadvantage when an affort is done to make Tet as an antitumor drug or tumor resistance reversor because the concentration of Tet that has been reported to kill tumor cells or reverse tumor resistance is much higher than safe concentration obtained in body. |
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