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  • Previous studies reported that combined administration of li

    2020-10-22

    Previous studies reported that combined administration of licorice/GL and TWHF/TP showed reduced toxicity and equal or even potentiated therapeutic efficacy when treating arthritis (YS et al., 2006, YS et al., 2008, Zhang et al., 2007). Our findings that GL reduced exposure to TP in rats confirmed the previously reported reduced toxicity of TP when co-administered with GL. But the vulnerable point is that less exposure to TP may also suggest attenuated efficacy. However, GL possesses potent anti-inflammatory activity; biochemical studies revealed that GL is an inhibitor of 11β-hydroxysteroid dehydrogenase, an enzyme responsible for the inactivation of cortisol, leading to the accumulation and enhanced activity of mtor inhibitors (Asl and Hosseinzadeh, 2008). Thus, combined administration of TP and GL is more likely to produce synergistic anti-inflammatory effect without attenuated therapeutic efficacy caused by GL induced less exposure to TP. In addition, GL has been reported to possess hepatic protective effect in drugs induced liver injury (Makino et al., 2008, Tsuruoka et al., 2009), which may benefit patients suffering from hepatotoxicity caused by TP. All these suggest justifications for the combined use of TP and GL in the treatment of inflammatory diseases and warrant further investigation for potential clinical applications.
    Conclusion
    Acknowledgments The present study was supported by the National Natural Science Foundation of China (Nos. 81173651 and 81274146), the Specific Fund for Public Interest Research of Traditional Chinese Medicine, the Ministry of Finance of China (No. 200707008), 2011׳ Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education, Technology Development Program of Nanjing Medical University (2013NJMU073) and partially supported by 111 Project (111-2-07).
    Introduction Following the approval of first tyrosine kinase inhibitor (TKI), imatinib, in 2001 by the US Food and Drug Administration (FDA), several TKIs have entered the market. Currently, TKIs are receiving considerable attention in cancer treatment owing to their excellent efficacy and low toxicity compared to those of traditional chemotherapeutic agents [1]. However, a major problem associated with TKI treatment is frequent clinical drug-drug interactions (DDIs) [[2], [3], [4], [5], [6], [7]]. Dasatinib (Sprycel®) and nilotinib (Tasignais®) are orally administered TKIs used for the treatment of chronic myeloid leukemia (CML) [2,5,8]. Both drugs extensively undergo cytochrome P4503A4 (CYP3A4)-mediated biotransformation, with the involvement of other enzymes to a lesser extent. In vitro studies have demonstrated their mechanism-based CYP3A4 inhibition [5,9]. Few studies have reported that dasatinib and nilotinib can increase the exposure of CYP3A4 substrates simvastatin and midazolam, respectively, in humans [2,4,5]. However, there is a lack of detailed information on the effect of dasatinib on other CYP3A4 substrates. While some research has been performed to determine the benefit of dasatinib and cyclosporine combination therapy [10,11], considering the chronic prescription patterns for TKIs, the current study was undertaken to fill the gaps in literature with regard to the effects of dasatinib and nilotinib on cyclosporine pharmacokinetics. Cyclosporine (NEORAL® Oral Solution, Novartis) is an immunosuppressant widely used in organ transplantation and many other clinical conditions [12]. It undergoes extensive hepatic and intestinal biotransformation mainly via the metabolizing enzyme, CYP3A4 [[12], [13], [14], [15]]. Considering the narrow therapeutic index of cyclosporine, the change in drug bioavailability may result in serious consequences, either increased toxicity or therapeutic failure [16]. Several reports indicated that CYP3A4 inhibitors or inducers can significantly change the bioavailability of cyclosporine [12].
    Materials and methods
    Results
    Discussion