Opinion
Insights into drug discovery from natural medicines using reverse pharmacokinetics

https://doi.org/10.1016/j.tips.2014.02.001Get rights and content

Highlights

  • Pharmacokinetic (PK) insights for advancing drug discovery from natural medicines (NMs) are highlighted.

  • A concept of ‘reverse pharmacokinetics’ is proposed to guide drug discovery from NMs.

  • PK study of NMs may inform the pharmacological basis and multicomponent drug design.

  • Challenges and critical issues in the PK study of NMs are discussed.

Natural medicines (NMs) are indispensable sources for the development of modern drugs. However, the targets for most natural compounds are unknown and the current pharmacokinetic evaluation systems developed for target-defined drugs may not be directly applicable to NM-based drug discovery, which is a major hindrance in bringing natural compounds to the clinic. Here, we propose the concept of ‘reverse pharmacokinetics’ and discuss how a ‘reverse pharmacokinetics’ perspective could help clarify key questions in modern drug discovery from NMs with validated clinical benefits, thereby strengthening the translational potential. Reverse pharmacokinetics can provide physiologically relevant clues to the target identification and mechanistic study of NMs, which may also innovate drug discovery for complex diseases. We anticipate that an evolving deep understanding of the novel mode of action of natural compounds with a reverse pharmacokinetic insight may improve discovery of both single ingredient and multiple-component modern drugs from NMs.

Section snippets

Drug discovery from NMs: promises and challenges

The development of molecular and structural biology, combinatorial chemistry, and high-throughput screening (HTS) has created a rapid process for designing and discovering drug candidates with high selectivity and high affinity to a defined molecular target. This has been a mainstream drug discovery paradigm since the 1990s and was initially heralded to promise a large drug discovery pipeline at decreased cost. In sharp contrast to this originally conceived picture, the pharmaceutical industry

Why ‘reverse pharmacokinetics’?

Target-based drug discovery is a process that moves from ‘laboratory to clinic’, whereas the reverse pharmacology-guided drug discovery of NMs features a reverse process of ‘clinic to laboratory’. Although such a difference is very clear, it seems that this discrepancy has not received sufficient consideration in drug development, where the same paradigm, strategy, theory, and methodology have been employed for target-based and reverse pharmacology-guided drug discovery. Pharmacokinetic

How might ‘reverse pharmacokinetics’ help development of NMs?

The purpose of ‘reverse pharmacokinetics’ is not to define whether the DMPK properties are appropriate but rather to determine the mechanistic links between the DMPK properties (e.g., absorption, distribution profile/kinetics, metabolism, pharmacokinetic profile, and the interaction with drug metabolizing enzymes/transporters, etc.) and in vivo pharmacological efficacies. For NMs with validated therapeutic benefits, knowledge obtained from the ‘reverse pharmacokinetics’ can be used for cluing

Methodological innovation in reverse pharmacokinetics of NMs

The DMPK study of natural compounds is a key process in reverse pharmacokinetics of NMs but represents an extremely challenging task. The complex and largely unknown chemical compositions, diverse physiochemical properties, low concentrations, extensive and elusive metabolism, biological matrix interference, and the lack of standard compounds superimpose the complexity on the DMPK study of NMs [81]. Fortunately, a panel of innovative strategies has recently been developed to address these

Concluding remarks

In contrast to the target-based design of drugs, reverse pharmacology-guided discovery of NMs starts from the phenotype screening of natural compounds for which the molecular targets and mechanisms are largely elusive. In spite of this huge difference, it seems that the same decision paradigms throughout the whole drug discovery pipeline have been applied to both types of drug discovery. This has led to a great dilemma in that many natural compounds are characterized with pleiotropic

Acknowledgments

Work in our laboratory was supported in part by the National Natural Science Foundation of China (numbers 81325025, 91029746, and 81273586); the Natural Science Foundation of Jiangsu province (BK2012026); and the Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics Projects (BM2012012).

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    These authors contributed equally to this work.

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