Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolide-induced Hepatotoxicity in Mice

Kong, Ling-Lei; Zhuang, Xiaomei; Yang, Haiying; Yuan, Mei; Xu, Liang; Li, Hua

doi:10.1038/srep11747

Cited by 41 publications

(35 citation statements)

References 47 publications

(59 reference statements)

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“…Further study indicated that the hepatotoxicity was more correlated to the hepatic TP exposure. P‐gp‐mediated clearance contributed significantly to TP detoxification (Kong et al, ). In the practice of Traditional Chinese Medicine, T. wilfordii is often used in combination with G. uralensis Fisch to relieve its toxicity (Liu et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetic studies of TP indicated that the concentration of the compound in liver was higher than in the other tissues (Shao et al, ; Xue et al, ), and high exposure of TP would aggravate its toxicity. Kong studying the role of P‐gp in TP clearance and detoxification found that the increase of TP exposure was correlated to its hepatotoxicity, and the hepatic exposure was more relevant to the toxicity (Kong et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Yan

Cao

et al. 2017

Phytotherapy Research

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Triptolide (TP) is an active ingredient isolated from Tripterygium wilfordii Hook. f. (TWHF), which is a traditional herbal medicine widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, its adverse reactions of hepatotoxicity and nephrotoxicity have been frequently reported which limited its clinical application. The aim of this study was to investigate the mechanism of glycyrrhetinic acid (GA) effecting on the elimination of TP in HK-2 cells and the role of the efflux transporters of P-gp and multidrug resistance-associated proteins (MRPs) in this process. An ultra performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) analytical method was established to determine the intracellular concentration of TP. In order to study the role of efflux transporters of P-gp and MRPs in GA impacting on the accumulation of TP, the inhibitors of efflux transporters (P-gp: verapamil; MRPs: MK571) were used in this study. The results showed that GA could enhance the elimination of TP and reduce the TP accumulation in HK-2 cells. Verapamil and MK571 could increase the intracellular concentration of TP; in addition, GA co-incubation with verapamil significantly increased the TP cellular concentration compared with the control group. In conclusion, GA could reduce the accumulation of TP in HK-2 cells, which was related to P-gp. This is probably one of the mechanisms that TP combined with GA to detoxify its toxicity. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Yan

Cao

et al. 2017

Phytotherapy Research

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“…Cancer cells may also overexpress efflux transporters under selection pressure that lead to drug resistance. P-gp inhibitors have been used to overcome drug resistance and improve intracellular drug levels, but these compounds have been associated with significant liver toxicity [17]. Other approaches include associating P-gp substrates to nanoparticles, which has been shown in vitro to reduce drug efflux [18].…”

Section: Traditional Approaches To Drug Delivery and The Need For Lonmentioning

confidence: 99%

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

McConnachie

et al. 2018

Journal of Drug Targeting

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The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine.

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“…This has been seen from preclinical experiments. The systemic and hepatic exposures of triptolide in mice were significantly increased by inhibiting P‐gp, and the increase in hepatic exposure was quantitatively correlated to the enhanced hepatotoxicity . However, there is still a lack of direct clinical evidence of the impact of biliary transporters on systemic and hepatic concentrations because of the difficulty in measuring drug concentrations in organs.…”

Section: Hepatic Transporters In Drug Interactionsmentioning

confidence: 99%

“…The systemic and hepatic exposures of triptolide in mice were significantly increased by inhibiting P-gp, and the increase in hepatic exposure was quantitatively correlated to the enhanced hepatotoxicity. 42 However, there is still a lack of direct clinical evidence of the impact of biliary transporters on systemic and hepatic concentrations because of the difficulty in measuring drug concentrations in organs. Clinical studies using positron emission tomography (PET)/single-photon emission computed tomography imaging and other advanced experimental methods in conjugation with mechanistic modeling may help improve our understanding of tissue distribution of a drug and its implications.…”

Section: S15mentioning

confidence: 99%

Role of Hepatic Drug Transporters in Drug Development

Liu

Sahi

2016

The Journal of Clinical Pharma

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Hepatic drug transporters can play an important role in pharmacokinetics and the disposition of therapeutic drugs and endogenous substances. Altered function of hepatic drug transporters due to drug-drug interactions (DDIs), genetic polymorphisms, and disease states can often result in a change in systemic and/or tissue exposure and subsequent pharmacological/toxicological effects of their substrates. Regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japan Pharmaceuticals and Medical Devices Agency have issued guidance for industry on drug interaction studies, which contain comprehensive recommendations on in vitro and in vivo study tools and cutoff values to evaluate the DDI potential of new molecular entities mediated by hepatic drug transporters. In this report we summarize the latest regulatory and scientific progress of hepatic drug transporters in clinical DDIs, pharmacogenetics, drug-induced liver injury (DILI), as well as methods for predicting transporter-mediated pharmacokinetics and DDIs. Keywords hepatic drug transporters, drug-drug interactions, pharmacokinetics, drug developmentLiver plays a critical role in drug metabolism and excretion of substances from the body. Hepatic elimination comprises multiple intrinsic processes: basolateral uptake of compounds from the blood side (extracellular space) into hepatocytes (phase 0), basolateral efflux from hepatocytes into the blood, phase I/phase II metabolism, and biliary excretion (phase III). 1 The influence of all of these processes in overall hepatic intrinsic clearance (CL int,all,h ) is described quantitatively by the extended clearance concept 2 :CL int, all, h = PS inf × CL int, met + CL int, bile PS eff + CL int, met + CL int, bile where PS inf , PS eff , CL int,met , and CL int,bile represent basolateral uptake intrinsic clearance, sinusoidal efflux intrinsic clearance, metabolic intrinsic clearance, and biliary efflux intrinsic clearance, respectively.Membrane transporters play a key role in the uptake clearance of many drugs from hepatic sinusoidal blood (PS inf ) and in the excretion of parent compounds and/or metabolites from hepatocytes into bile (CL int,bile ) or the systemic circulation (PS eff ). 3

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Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolide-induced Hepatotoxicity in Mice

Cited by 41 publications

References 47 publications

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

Role of Hepatic Drug Transporters in Drug Development

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