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Translational research is an emerging discipline that aims to fill the gap through the whole pipeline from bench to bedside. This review highlights the importance and urgency of incorporating translational research into the study of pharmacokinetic herb drug interactions (PHDI), based on an intensive discussion on the controversial and inconsistent reports from preclinical to clinical, in vitro to in vivo, and across different studies concerning PHDI. Current controversial and dispersed reports confer poor translational capacity of experimental research data to guiding the clinical practices. We propose that the herbal complexities in their chemical compositions, biphasic and tissue-specific effects of enzymes, and the present incomplete understanding of the disposition properties of herbal medicines themselves; and the enzymatic complexities in the species differences, individual genotype and phenotype, differential regulation during healthy and pathological conditions, substrate dependent modulations, and their interplay with transporters, collectively constitute the major translational blocks in PHDI from experimental research to daily clinical practice. In clinical considerations, this review indicates that PHDI are far from clear based on the isolated preclinical findings, and that the intestine is a much more susceptible site than liver when subjected to herbal regulations, and that enzymatic induction could be more predominant than inhibition upon chronic ingestion of herbal medicines. Hopefully, this review would be helpful for better understanding the nature of hurdles in PHDI research, and for igniting the future translational research initiatives.

Quinones represent a very important class of compounds found in nature and for the chemically synthesized drugs. The present study was designed to elucidate the intestinal first pass metabolic pathways in vivo and in vitro, of tanshinone IIA (TS), a derivative of phenanthrene-quinone isolated from Salvia miltiorrhiza. Five metabolites, proposed to be TS catechol glucuronides (two position isomers), dehydrotanshinone IIA and its two catechol glucuronides, were identified from the rat intestinal homogenates after oral administration of TS. TS metabolism was further conducted in the subcellular system including cytosol, microsomes, mitochondrial and S9 under both phase I and phase II metabolic conditions. TS underwent negligible metabolism in all of the subcellular systems under phase I metabolic condition using NADPH as the cofactor. However, significant and substantial metabolic elimination of TS was observed in the cytosol and S9 fractions, while not in the microsomes fractions, when both NADPH and UDPGA were added. Two TS catechol glucuronides were identified from such an in vitro metabolic medium. Dicoumarol, a specific inhibitor of the NAD(P)H dependent quinone oxidoreductase (NQO1), significantly inhibited the metabolic elimination of TS in a noncompetitive way, suggesting that NQO1 was responsible for the quinone reduction of TS to form the catechol intermediate. The catechol intermediate failed to be detected directly was proved to be highly unstable and autoxidized back to TS accompanied with hydrogen peroxide generation. Dicoumarol exhibited a significant inhibitory effect on the hydrogen peroxide generation, further supporting that the reduction of TS was catalyzed by NQO1. The absolute bioavailability of TS was significantly enhanced by oral dicoumarol pretreatment. In conclusion, a novel intestinal metabolic pathway for quinones, NQO1 mediated reduction and subsequent glucuronidation, was determined using TS as a model compound. This study should be helpful for the general understanding of quinones absorption and intestinal first pass metabolism.

Recently, there is a global trend of using herbal medicines to treat various chronic diseases and promote health. But the controversy over the safety and efficacy of herbal medicines is a focus of attention, primarily because of the many unknown and unrevealed natures of herbal medicines, which strongly restricts their application and development. Pharmacokinetics is a bridge linking the herbal medicines and their pharmacological responses. It is assumed in traditional pharmacokinetics that an excellent drug should have appropriate pharmacokinetic behaviours and its pharmacological effect is related with plasma drug concentrations. However, most herbal medicines exhibit excellent pharmacological responses despite poor pharmacokinetic behaviours. As most drugs are intracellulartargeted, we put forward cellular pharmacokinetic-pharmacodynamic strategy, which is focused on the intracellular fate of drugs. This strategy could partially explain the marked pharmacological activities of herbal medicines from their intracellular pharmacokinetic behaviours, rather than their plasma concentrations. It is a helpful complementarity to traditional pharmacokinetics, and takes a potential role in the research and development of new herb-origined drugs. In this review, the pharmacokinetics-pharmacology disconnections of herbal medicines (such as ginseng, berberine and danshen) are retrospected. Then our proposed cellular pharmacokineticpharmacodynamic strategy, its characteristics, as well as its research procedures are described, followed by the subcellular distributions of drug transporters and metabolic enzymes which are the determinants of cellular pharmacokinetics-pharmacodynamics. Finally, our successful applications of cellular pharmacokinetic-pharmacodynamic strategy in elucidating ginsenoside Rh2 as an adjuvant agent and tanshinone IIA as an anticancer agent are illustrated.

Accompanying with hot discussions on developing multi-target drugs for the therapy of multi-gene diseases, herbal medicines are receiving more and more attention worldwide in both academic and industrial fields. Pharmacokinetic and metabolic research is one of the important issues for intensive understanding of therapeutic benefits/risks of herbal medicines. The qualitative and quantitative analysis of herbal medicines, which is a prerequisite for pharmacokinetic and metabolic evaluations, remains a great challenge because of the intrinsic complexity of herbal medicines. This paper provides a review on the recent development of qualitative and quantitative methodologies on herbal medicines analysis. Powerful hybrid mass spectrometric tools such as Q-TOF and IT-TOF are highly useful for both the qualitative and quantitative analysis of complicated components. In the past decade, some universal useful strategies to the qualitative and quantitative analysis and pharmacokinetic assessment of complicated herbal components have been also proposed. Nonetheless, it is urgent to develop additional strategies to resolve the critical challenges underlying herbal analyses, such as the lack of authentic compounds, the difficulties in information processing, and the elimination of complex matrixes interferences.

Herbal medicines (HMs) are gaining more and more attention all over the world, because of their significant curative effect in treating multi-factorial diseases. Recently, the in vivo and in vitro metabolism study of HMs has become an important issue because these data can help us to better understand the efficacies and toxicities of HMs. However, the integral metabolism profile of HMs is confronted with many challenges: 1) HM is a multi-component system; 2) most components are unknown (nontarget); 3) trace of components in HM. Given the challenges described above, the demand for more powerful bioanalytical tools and strategies that are adequate for integral metabolism profile of HMs' multi-components has increased. In the past few years, newer methods, or adaptations to methods, have been published, and this review will attempt to discuss new improvements in strategies and methodologies for HMs' multi-component ADME evaluation. In particular, improvements have been reported for experimental approaches to pharmacokinetics study of HMs, as well as strategies applied to metabolites characterization of HMs' multi-components, and the metabolic interactions between ingredients in HMs, including advance and proposed strategy: "chemical fishing" based strategy for metabolic interactions of HMs.