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

From: Pharmacokinetics of Chinese medicines: strategies and perspectives

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