Study on Long-term Toxicity and Toxicokinetics of Phytolaccae Radix

OBJECTIVE To obtain the “quantity-time-toxicity” relationship by studying the long-term toxic reaction and toxicokinetics of Phytolaccae Radix to rats. METHODS Rats were given low, medium and high doses of aqueous extracts of Phytolaccae Radix for 120 d to observe the general condition, body weight, blood biochemical indexes, hematological indexes, urine indexes, early injury indexes, organ indexes and pathological examinations of the rats. And on 1, 28, and 120 d, blood was collected from each group of rats, and LC-MS/MS method was used to determine the plasma concentration of esculentoside A(EsA) and fit the toxicokinetic parameters. RESULTS Compared with the blank control group, the rats in the middle and high-dose groups were significantly reduced in body weight(P<0.05), sluggish and reduced in activity, white blood cell in the blood were significantly increased(P<0.05 or P<0.01), urine protein in the urine was significantly increased(P<0.05 or P<0.01), kidney injury molecule 1 increased significantly(P<0.05 or P<0.01), kidney-to-body ratio increased significantly(P<0.05), histopathological examination directly observed renal tubular damage and renal interstitial nephritis in the kidneys, and kidney damage in rats. The toxicokinetic study showed that when the same dose was administered, the C_max and AUC_0-t of EsA in the plasma of each group of rats increased with the extension of the administration time. At the same time point of administration, the C_max and AUC_0-t of EsA in the plasma of rats in different doses groups increased with the increase of the dose. CONCLUSION Phytolaccae Radix has obvious nephrotoxicity when it is repeatedly administered for 120 d. EsA is one of the toxic components of Phytolaccae Radix. The relationship of “quantity-time-toxicity” of Phytolaccae Radix is that the greater the dose and the longer the period of administration, the higher the EsA exposure in rat plasma, the stronger the nephrotoxicity of Phytolaccae Radix.