Table 1.

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

Strategy	Advantages	Disadvantages
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