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

Chin-Tsung Ting,Tung-Hu Tsai,Yung-Yi Cheng

doi:10.3390/molecules22071034

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its global annual incidence is rising [1,2]
In the majority of patients with HCC who do not meet the criteria for curative therapies, recurrence after curative therapies or extra-hepatic spread should be treated with another palliative treatment, such as transarterial chemoembolization (TACE), chemo-radiotherapy or alternative therapies
The aim of this study is to investigate the pharmacokinetic mechanism of the herb-drug interaction between the LDXGT formulation and sorafenib

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its global annual incidence is rising [1,2]. Molecules 2017, 22, 1034 best therapy for HCC is still surgical hepatic resection [3,4]. Other treatments, such as percutaneous ablation [5] and liver transplantation [6], offer a high probability of complete response in patients with early and intermediate stage HCC. Less than 30% of patients with HCC can be treated with curative therapy, and the overall five-year survival rate following resection has remained as low as 35–50% due to the high recurrence rate in the remnant liver. In the majority of patients with HCC who do not meet the criteria for curative therapies, recurrence after curative therapies or extra-hepatic spread should be treated with another palliative treatment, such as transarterial chemoembolization (TACE), chemo-radiotherapy or alternative therapies

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