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Open AccessArticle

Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats

by Chin-Tsung Ting 1,2, Yung-Yi Cheng 1 and Tung-Hu Tsai 1,3,4,5,*
1
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
2
Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei 10629, Taiwan
3
Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan
4
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
5
Department of Chemical Engineering, National United University, Miaoli 36063, Taiwan
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(7), 1034; https://doi.org/10.3390/molecules22071034
Received: 4 June 2017 / Accepted: 19 June 2017 / Published: 22 June 2017
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans. View Full-Text
Keywords: hepatocellular carcinoma; Chinese herbal medicine; Radix Gentianae formulation; sorafenib; pharmacokinetics hepatocellular carcinoma; Chinese herbal medicine; Radix Gentianae formulation; sorafenib; pharmacokinetics
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MDPI and ACS Style

Ting, C.-T.; Cheng, Y.-Y.; Tsai, T.-H. Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats. Molecules 2017, 22, 1034.

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