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Chinese traditional medicine has provided, since ancient times, a basis for health care and medicine to the Chinese nation and for China's national stability. Identification of the constituents responsible for therapeutic and undesired effects of Chinese herbal medicines is a type of key research facilitating the modernization of these medicines. For a complex Chinese herbal medicine, multi-compound pharmacokinetic research is a useful approach to identifying its constituents that are bioavailable (in their unchanged and/or metabolized forms) at loci responsible for the medicine's therapeutic action and to characterizing the compounds' disposition and pharmacokinetics related to the action. In addition, such pharmacokinetic research is also useful for identifying herbal compounds associated with the medicine's adverse effects and drug-drug interaction potential. Over the past decade, great advances have been achieved in the theory, methodology, associated techniques, and their application of such multi-compound pharmacokinetic research, which has become an emerging field in pharmacokinetics. In this perspective, we elaborate on the methodology, technical requirements, and key analytical techniques of multi-compound pharmacokinetic research on Chinese herbal medicines, describe research examples regarding investigation of pharmacokinetics and disposition of a class of bioactive herbal constituents (ginsenosides of Panax notoginseng root) and pharmacokinetics-based identification of potential therapeutic compounds from a dosed Chinese herbal medicine (LianhuaQingwen capsule), and discuss follow-up development for the multi-compound pharmacokinetic research.
RESUMO
Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene) was first identified from white hellebore (Veratrum grandiflorum) root and began to attract interest when its presence in red wine and cardiovascular activities were reported, leading to speculation of its contribution to the 'French paradox'. Besides the cardiovascular protection, potential health benefits of resveratrol include calorie restriction-like effects, cancer prevention and adjunctive therapy, and neuroprotection. In order to achieve translational applications of these potential benefits, pharmacokinetic research was performed for plasma pharmacokinetics and related disposition of orally dosed resveratrol. This paper summarizes the known human pharmacokinetic characteristics of resveratrol after oral administration and various attempts to improve its systemic exposure level from the perspectives of systemic exposure and in vivo process. However, available pharmacokinetic data of resveratrol has raised conundrums that limit translating potential benefits to clinics: (1) differences between the unchanged resveratrol used in bioactivity studies and its major circulating forms (i.e., metabolites) after dosing; (2) resveratrol's test concentrations used to exert in vitro bioactivities related to the benefits significantly higher than the compound's clinically achievable concentrations; (3) resveratrol's concentrations achievable (estimated from the pharmacokinetics) from doses used to produce in vivo efficacy significantly lower than the effective concentrations found in studies of related action mechanism (suggesting unreliability of test mechanism). In the last part of this review, we provide recommendations for future pharmacokinetic investigations of resveratrol, including a more systematic investigation of systemic exposure to resveratrol metabolites, their access to in vivo loci responsible for the benefits, and their disposition in target cells; an investigation of colon-luminal exposure to resveratrol and its metabolites for accessing colonic microbiota; and a multi-compound pharmacokinetic investigation of red wine.
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Methyl (S)-4-(6-amino-9H-purin-9-yl)-2-hydroxybutanoate (DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9H-purin-9-yl)-2-hydroxybutyric acid (DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90％–159％. The mean terminal half-lives of DZ2002 and DZA were 0.3–0.9 and 1.3–5.1 h, respectively. The sample preparation method illustrated here may be adopted for de-termination of other circulating ester drugs and their acid metabolites in rodents.
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Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.