Nobiletin potentiates paclitaxel anticancer efficacy in A549/T xenograft model: Pharmacokinetic and pharmacological study.

BACKGROUND: Nobiletin (N), a polymethoxylated flavone from citrus fruits, enhanced anti-cancer effects of paclitaxel (PTX) in multi-drug resistance (MDR) cancer cells via inhibiting P-glycoprotein (P-gp) in our previous report. But the in vivo chemo-sensitizing effect of nobiletin is unknown. Moreover, considering the nonlinear pharmacokinetics and narrow therapeutic window of PTX, drug-drug interaction should be explored for using nobiletin with PTX together. PURPOSE: In this study, we wanted to explore whether nobiletin could affect the pharmacokinetic (PK) behavior of PTX and reverse drug resistance in vivo as well as the corresponding mechanisms. STUDY DESIGN AND METHODS: Accurate and sensitive UPLC-MS/MS method was developed for the detection of PTX, and was applied to the pharmacokinetic study in rats. In vivo anti-MDR tumor study was carried out with A549/T xenograft nude mice model. Immunohistochemistry and western blot analysis were used for evaluating the levels of P-gp, Nrf2, and AKT/ERK pathways in MDR tumors. RESULTS: Nobiletin significantly enhanced the therapeutic effects of PTX, and inhibited the MDR tumor sizes in the A549/T xenograft model, while PTX or nobiletin alone did not. We found that nobiletin increased the PTX concentrations in tumor tissues but did not affect the PK behavior of PTX. Notably, Nrf2 and phosphorylation of AKT/ERK expression in MDR tumor tissues were significantly inhibited by giving nobiletin and PTX together. However, nobiletin did not affect the expression of P-gp. CONCLUSION: Nobiletin reversed PTX resistance in MDR tumor via increasing the PTX content in the MDR tumor and inhibiting AKT/ERK/Nrf2 pathways, but without affecting the systematic exposure of PTX, indicating that nobiletin may be an effective and safe MDR tumor reversal agent.

Drug metabolism and pharmacokinetics of nanodrugs from Chinese medicines and natural products.

Over the past few years, nanoscale Chinese medicine has become one of focuses in modern Chinese medicine research. There is an increasing need for a more systematic study on the basic issues involved in traditional Chinese medicine and a more active participation of researchers in the application area of nanoscale traditional Chinese drugs. In this review, author analyzed the current applications of nanotechnology in research and development of drugs from natural products and herbal medicines involving traditional Chinese medicines, and also discussed the bio-medicinal evaluation issues on ADME including bio-distribution and metabolism of nanodrugs. Author noted that great challenges faced in nanodrugs from herb drugs and natural products are the follows: (1) the first challenge is to prepare nanodrug delivery system and quantitatively evaluate the therapeutic effects and safety; (2) the second challenge is to clarify the concrete metabolism course; and (3) the third challenge is to study the pharmacokinetics of nanodrugs.

Herb-drug interactions involving drug metabolizing enzymes and transporters.

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity. The herb-drug combinations may reduce a drug efficacy and lead to treatment failure when long-term administration. Case reports detailing serious clinical adverse reactions have promoted studies on the interactions between herbs and drugs. This review highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Drug transporters are widely present in body and play an important role in the absorption, distribution, excretion and metabolism, efficacy, and toxicity of drugs. Investigation of transporters has developed rapidly since 1990s, the effects of many transporters on the pharmacokinetics of drugs and herb-drug interactions have been reported. Some concepts on drug transporters issued experimentally and clinically drug-drug and herb-drug interactions have applied in many studies. Methodology studies are very important for understanding the mechanism, considerations and evaluation of experiments and clinical studies on drug metabolizing enzymes and transporters in drug-drug interactions.