Hepatotoxicity and pharmacokinetics of cisplatin in combination therapy with a traditional Chinese medicine compound of Zengmian Yiliu granules in ICR mice and SKOV-3-bearing nude mice.
BACKGROUND
Cisplatin (CDDP) is a highly effective chemotherapeutic agent used for therapy of many tumors and has been limited by its toxicity. Zengmian Yiliu granule (ZMYL), a compound preparation of traditional Chinese medicines, has been used in clinic as a complementary and alternative medicine for attenuating CDDP-induced toxicities and enhancing the tumor therapeutic effect of CDDP. The aim of the present study is to investigate hepaprotective effect of ZMYL against CDDP-induced hepatotoxicity. Further, the pharmacokinetic characteristics of CDDP in SKOV-3-bearing nude mice were observed.


METHODS
The ICR mice were dosed orally with ZMYL for 7 days and then CDDP was injected intraperitoneally at a dose of 45 mg/kg body weight. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to evaluate the liver function. The total glutathione (T-GSH), reduced glutathione (GSH) and glutathione S-transferase (GST) levels were determined to evaluate the oxidant damage in liver homogenates. Tissue pathological change in liver was conducted by light microscopy analysis. The pharmacokinetic and tissue distribution of free and total platinum (Pt) after dosing of CDDP alone and combination with ZMYL were determined in SKOV-3-bearing nude mice by ICP-MS.


RESULTS
Oral administration of ZMYL prior to the CDDP treatment could prevent the CDDP-induced in lifting of ALT and AST, reduction of T-GSH, R-GSH and GST, and some histopathological alterations in ICR mice. Some differences in pharmacokinetic parameters between the two groups have been observed in higher CL and decreased MRT of free platinum (Pt) in plasma and total Pt in spleen in CDDP co-administration with ZMYL group. It indicated CDDP was cleared more quickly from blood and spleen, and could reduce the accumulation and toxic possibility of CDDP in combination with ZMYL.


CONCLUSIONS
ZMYL could be used as a beneficial supplement, which could attenuate CDDP-induced hepatotoxicity during CDDP chemotherapy and did not disturb the pharmacokinetics fate of CDDP significantly.
The Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of TCM Complex Prescription, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.|School and Chemical and Environmental Engineering, Shanghai Institute of Techanology, 100 Haiquan Road, Fengxian, Shanghai, 201418, People's Republic of China.
Can
C
Gong
Department of Gynaecology, Shanghai Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.
Lin
L
Qian
Department of Gynaecology, Shanghai Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.
Hong
H
Yang
The Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of TCM Complex Prescription, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.
Li-li
LL
Ji
Research Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.
Hai
H
Wei
Research Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China.
Wen-bin
WB
Zhou
Department of Gynaecology, Shanghai Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. qicongxzq@aliyun.com.
Cong
C
Qi
The Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of TCM Complex Prescription, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. wchcxm@hotmail.com.
Chang-hong
CH
Wang
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002945:Cisplatin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008516:Medicine, Chinese Traditional; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D010946:Plants, Medicinal; D010984:Platinum / Q000378:metabolism / Q000627:therapeutic use; D013154:Spleen / Q000378:metabolism
D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D010984:Platinum; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D002945:Cisplatin