Towards polypharmacokinetics: pharmacokinetics of multicomponent drugs and herbal medicines using a metabolomics approach

Abstract

Determination of pharmacokinetics (PKs) of multicomponent pharmaceuticals and/or nutraceuticals (polypharmacokinetics, poly-PKs) is difficult due to the vast number of compounds present in natural products, their various concentrations across a wide range, complexity of their interactions, as well as their complex degradation dynamics in vivo. Metabolomics coupled with multivariate statistical tools that focus on the comprehensive analysis of small molecules in biofluids is a viable approach to address the challenges of poly-PK. This paper discusses recent advances in the characterization of poly-PK and the metabolism of multicomponent xenobiotic agents, such as compound drugs, dietary supplements, and herbal medicines, using metabolomics strategy. We propose a research framework that integrates the dynamic concentration profile of bioavailable xenobiotic molecules that result from in vivo absorption and hepatic and gut bacterial metabolism, as well as the human metabolic response profile. This framework will address the bottleneck problem in the pharmacological evaluation of multicomponent pharmaceuticals and nutraceuticals, leading to the direct elucidation of the pharmacological and molecular mechanisms of these compounds.

Figure 1

LC-MS protocol for xenobiotic intervention studies with and without the incorporation of metabolomics. Iv: intravenous; po: oral; EIC: extracted ion chromatogram; PLS-DA: partial least squares-discriminant analysis; TIC: total ion chromatogram.

Figure 2

Major aconitum alkaloids in aconite roots and in vitro metabolites of aconitine [–28]. Me: methyl group; Et: ethyl group; Ac: acetyl group; Bz: benzoyl group; As: anisoyl group.

Figure 3

Dynamic concentration profile of bioavailable Pu-erh tea polyphenols due to in vivo absorption, and hepatic and gut bacterial metabolism, as well as the human metabolic response profile. (a) Urine concentration-time course of some representative substances, intact polyphenols, metabolites of the absorbed polyphenols, and altered endogenous metabolites, after Pu-erh tea intake; (b) effect of Pu-erh tea intake on human urine metabolite endpoints. (left panel) Heatmap showing differences in altered endogenous metabolites detected from the metabolome after Pu-erh tea intake (postdose) as compared to predose metabolome. (I) metabolomic changes at 24 h postdose relative to predose; (II) 2-week postdose versus predose; (III) 2-week washout versus predose. Each cell in the heat map represents the fold change between the two time points (e.g., postdose versus the predose) for a particular metabolite. (right panel) 3D PCA scores plot of urinary metabolic profiles at predose, 24 h postdose, 2 week postdose, and 2 week washout postdose; (c) correlation of intact polyphenols, metabolites of the absorbed polyphenols, and altered endogenous metabolites in response to Pu-erh tea exposure. The relationships among the three groups of compounds were visualized in the form of correlation maps, which are displayed by red (positive) or blue (negative) lines.

Figure 4

Research framework to integrate the dynamic concentration profile of bioavailable xenobiotic molecules due to in vivo absorption and the hepatic and gut bacterial metabolism, as well as the human metabolic response profile.