br Introduction Extracts of Tripterygium wilfordii Hook F

Introduction Extracts of Tripterygium wilfordii Hook F (TWHF) have been used for centuries as the drug of choice for treatment of rheumatoid arthritis, a disease of autoimmune dysfunction, in traditional Chinese medicine (Bao and Dai, 2011, Tao et al., 2002). Triptolide (TP), a structurally distinct diterpene triepoxide isolated from TWHF, has been identified as the primary active ingredient responsible for its biological activities since 1970s (Kupchan et al., 1972). TP has been reported to possess a wide variety of pharmacological activities, including anti-inflammatory, immunosuppressive, anti-cystogenesis and antitumor activities (Leuenroth et al., 2007, Liu, 2011). Nevertheless, the application of TP in the clinical settings has been largely restricted because of its narrow therapeutic window and severe toxicity to digestive, reproductive and hematopoietic systems (Liu et al., 2010, Liu et al., 2011, Ni et al., 2008). For this reason, diverse structure modifications of TP are under investigation for improved safety (Zhou et al., 2012). In vitro studies indicated that TP is converted into mono-hydroxylated metabolites by cytochrome P450s, in which CYP3A4 is the primary isoform responsible for the hydroxylation of TP (Li et al., 2008). Pretreatment with dexamethasone, a CYP3A inducer, significantly increases the Pemetrexed disodium hemipenta hydrate of TP in male rat liver microsomes and decreases TP-induced hepatotoxicity in rats (Ye et al., 2010). Moreover, knockout of hepatic P450 reductase results in markedly increased blood and tissue levels of TP, as well as apparently exacerbated toxicity caused by TP in mice (Xue et al., 2011). Thus, hepatic P450s, especially CYP3A, play a critical role in the metabolic detoxification of TP. Glycyrrhizin (GL) is the principal bioactive component of licorice, which has been extensively used in traditional Chinese medicine for the treatment of various inflammatory diseases (Eisenbrand, 2006) or as a tonifying herbal medicine (Zhang and Ye, 2009). Recent studies have also found that combined administration of licorice/GL and TWHF/TP showed potentiated efficacy and reduced toxicity on treatment of rheumatoid arthritis in rat collagen-induced arthritis model (YS et al., 2008, Zhang et al., 2007) as well as in clinical applications (YS et al., 2006). GL has been reported to selectively influence the activity of CYPs (Hu et al., 1999, Paolini et al., 1998). Experiments in healthy volunteers demonstrated that GL induced CYP3A4-dependent sulfoxidation of omeprazole (Tu et al., 2010). Several pharmacokinetic studies also suggested that GL could significantly alter the metabolic fate of multiple co-administered drugs in rats (Lin et al., 2009, Matta et al., 2009, Mu et al., 2006).
Materials and methods
Results
Discussion TP has aroused extensive explorations because of its potent anti-inflammatory, immune-suppressive and antitumor activities. Notwithstanding these, TP has yet to enter Phase II clinical trials owing to its severe toxicity (Zhou et al., 2012). TP could induce amenorrhea in female rats (Liu et al., 2011) as well as sperm damage in males (Ni et al., 2008) at very low doses. Furthermore, previous studies in our laboratory showed that hepatotoxicity seemed to be one of the most severe adverse reactions of TP, demonstrated by both biochemical and morphological changes (Fu et al., 2011, Liu et al., 2010, Wang et al., 2013). Therefore, it is crucial to comprehensively understand the pharmacokinetic profiles of TP with the aim of improving its safety.