Table 1 The advantages and disadvantages of strategies/approaches for the pharmacokinetic study of Chinese medicines

Classic PK-PD

PK study adopts the same strategy tailored for western medicines which focuses on systemic exposures

PD study usually measures limited pharmacological parameters/clinical endpoints, except for poly PK-PD

Can identify bioactive components with ideal PK property for new drug discovery from CMs

PK–PD profiles of limited number of components may not describe the complex dose-exposure-efficacy/toxicity relationship and explain the multi-component multi-target action mode rooted from the chemical complexity of the herb/compound formulas

Systemic exposures of most components are too low to account for the holistic benefits of CMs

The interactions with gut microbiota prior to intestinal absorption were ignored

Components targeting at cellular components show poor PK–PD relevance

 PK of chemical marker/main component/multi-component

Obtains individual PK profile of chemical marker/main components/multi-component of CMs

Restricted by herbal chemistry knowledge, availability of authentic compounds and analytical technology

Chemical markers documented for quality control may not be the abundant or specific in the herb

Main compounds may not show ideal PK property and be main circulating components

 Surrogate PK

Describes pharmacokinetic profiles of CMs using surrogate PK markers (prototypes and/or metabolites) which exhibit significant exposure, show good dose-exposure correlation, and exhibit good correlation or prediction of drug efficacy, safety, or factors that affect exposure

Less time-consuming, more readily be translated to industry or clinical practice

It’s difficult to find compounds which show both high exposure and good dose-exposure and efficacy correlation

The PK profiles of the surrogate marker may subject to changes when the amounts/compositions of co-exiting components vary

 Integrated PK

Describe the holistic PK characteristics of CMs using the integral PK of components bearing the same core structure

Establish dose-exposure and efficacy relationship for a group of, not individual, bioactive components

Bioactivity/toxicity-weighting integral PK approach correlated better with efficiency/toxicity

Establishment of structure–activity relationship is limited by the availability of authentic compounds

The metabolites of the components which are bioactive and the main circulating form should be included for calculating integral PK

Bioactivity/toxicity-weighting integral PK will change with specific bioactivity/toxicity tested

 Poly PK-PD

Applies metabolomics for PK and PD profiling

Allows the correlation of the perturbations of endogenous metabolic network with the disposition of the drug-related components

Monitors global/specific metabolic shifts using untargeted/targeted metabolomics approaches

The analyte coverage and detection sensitivity rely on the analytical techniques

Only those gut microbial metabolites and host-microbial co-metabolites entering the circulating system are possibly detected

Cellular PK-PD

Determines the cellular drug accumulation and intracellular drug distribution and correlates the cellular dynamic drug disposition with its intracellular target binding and efficacy

Be more relevant to drug efficacy than plasma drug exposure when drug targets localize inside the cells

Drugs entering cell are limited by transporters and drug-metabolizing enzymes

Intracellular drug concentrations are generally low

Relies on the specificity and sensitivity of imaging techniques

Performed in vitro, complementary to traditional PK to establish PK–PD relevance

Global PK-PD

Combines classic PK–PD which measures systemic drug exposure and extracellular and/or membrane targets, cellular PK–PD which examines cellular drug distribution and intracellular targets, with presystemic PK–PD which determines relevance between gut drug exposure and microbial targets

The association study of gut microbial alterations and host metabolic shifts allows estimating the contribution of gut microbiota to the health benefits of CMs

Adding a compartment describing individual microbial structure/function data into the PBPK modeling allows more precise prediction of inter-individual variability in drug disposition and response

Requires powerful instrumental platform and multivariate statistical tools to deal with very complex sample analysis and data analysis and interpretation