Editorial
Current Drug Metabolism, 2012, Vol. 13, No. 5
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Editorial Absorption, Disposition, and Pharmacokinetics of Herbal Medicines: What and How? Botanical products are gaining growing popularity and increasing use worldwide, but they are very diverse with regard to product nature. Some products are identical to medicines, while others come close to food. When a botanical product at a defined dosage can be proven to have a clear medicinal effect for a defined medicinal purpose and presented with a medicinal claim, the product should be regarded and registered as an herbal medicine [1]. Such medicinal botanical products are expected to meet comparable standards for synthetic drugs with respect to efficacy, safety, and pharmaceutical quality. For the herbal medicine, an important scientific question from pharmaceutical scientists deals with the absorption, disposition (including distribution, metabolism, and excretion), and pharmacokinetics (ADME/PK) of their bioactive constituents after dosing, which is critically important in identifying the medicinal principles responsible for the medicine’s therapeutic effects and in establishing the risk-benefit relationship [2-4]. The ADME/PK information is also crucial to establishment of a therapeutic regimen providing optimal efficacy with minimal toxicity for an herbal medicine. In this issue, we hope to illustrate the current state of ADME/PK science relating to herbal medicines and the associated phytochemicals. Unlike synthetic drugs, herbal medicines are complex chemical mixtures. The effect of an herbal therapy is not necessarily the result of a single mechanism induced by a single ingredient, but a range of activities of multiple compounds working together to produce a medicinal benefit. Accordingly, the ADME/PK study of an herbal medicine should involve elucidating the systemic exposure to the multiple herbal compounds from the administered medicine and understanding their fates in the body. The aim of study is to bridge the gap between the complex chemical composition of the herbal medicine and its medicinal effects. Recently, a methodology has been established to implement multi-compound ADME/PK studies of herbal medicines [5,6], which is referred to as “ADME/PK-bridged pharmacology-to-chemistry” methodology. The study is performed to identify, from a certain group of pharmacologically active constituents present in an herbal medicine, the compounds that have favorable PK properties and substantial, medicine dose-dependent systemic exposure levels after administration of the medicine. In this issue, Li et al. describes another methodology for performing multi-compound ADME/PK studies of herbal medicines [7], which is designated as “ADME/PK-bridged chemistry-to-pharmacology” methodology. These authors identified, from a broad range of chemical constituents present in a standardized extract of Ginkgo biloba leaves (GBE50 extract; including 72 terpene lactones, flavonoids, and carboxylic acids), the ginkgo compounds that could traverse the enterohepatic barrier after p.o. administration of the extract to rats, as well as the chemical forms in which the ginkgo compounds entered considerably the systemic circulation. In addition, they also revealed the relevant mechanisms governing the intestinal absorption and presystemic elimination for the tested ginkgo compounds. With such research information, pharmacological and toxicological scientists can be aware which herbal compounds are worth their testing. These multicompound studies provide guidance for further systematic investigation into chemical basis responsible for the in vivo biological effects produced by herbal medicines. Drug exposure is a crucial determinant of drug efficacy and safety. The systemic exposure to the herbal compounds after ingestion of herbal medicines is also the subject of contributions by Zhang et al. [8] and Yan et al. [9]. In the practice of Chinese traditional medicine, multiple herbs are commonly used together for combination therapy, which follows the rule of drug synergism and compatibility. Measuring systemic exposure to each component herb is important for understanding the roles of the individual herbs in the combination therapy. Zhang et al. describe a joint LC/IT-MS- and GC/MS-based measurement of herbal constituents and the metabolites occurring in rat plasma, bile, and urine for each of the four component herbs from p.o. administered Qishen yiqi pills, a standardized herbal medicine. In addition, four major plasma herbal constituents of known pharmacological activities were further assessed for their pharmacokinetics. Most ADME/PK studies of herbal medicines have focused on the major constituents present in an herbal medicine, while ADME/PK of components with low content in herbal medicines is often ignored. However, the most abundant ingredients do not necessarily produce the highest concentrations of the compounds or their metabolites in vivo. Yan et al. give an example demonstrating how the ADME/PK study can reveal potential importance of a low content ingredient (Z-butylidenephthalide) to the herbal bioactivities of the medicinal herb Ligusticum chuanxiong rhizomes. The results from drug metabolism study can significantly enhance knowledge on the molecular mechanisms of chemical-induced beneficial or toxic effects. Complexity in chemical nature and structural diversity between phytochemicals and synthetic drugs often makes the metabolite analysis for herbal medicines challenging. Yang et al. describe recent developments in methodologies and techniques that have been used for detection and identification of in vivo metabolites of a variety of herbal compounds, including flavonoids, alkaloids, anthraquinones, terpenoids, etc [10]. Significant discrepancy in concentrations of phytochemicals is often observed between in vitro studies related to their biological activities and the associated in vivo pharmacokinetic studies [11,12]. Zhang et al. present very low oral bioavailability and systemic exposure levels of several important phytochemicals, including the saponin ginsenosides from Panax ginseng roots (Renshen), the alkaloid berberine from Coptis chinensis rhizomes (Huanglian), and phenolic acids and diterpenoids from Salvia miltiorrhiza roots (Danshen), which are hardly correlated with their pharmacological activities [13]. These authors propose investigation into the intracellular fate of phytochemicals, either in parallel with or in addition to the conventional ADME/PK study, to narrow the gap between pharmacokinetics and medicinal effects for herbal medicines. Current knowledge on ADME/PK of phytochemicals has come largely from flavonoids, especially flavonols, isoflavones, and catechins [14-17], while the understanding for other classes of herbal compounds is relatively scarce. Like the flavonoids, many saponins also exhibit pharmacological properties and are believed to be key ingredients triggering biological activities of many herb medicines. Yu et al. summarize and update the understanding of ADME/PK of some important saponins from Chinese medicinal herbs [18]. Obtaining a better understanding of drug gaining access to its target of action is essential for improving the efficacy and safety of drug therapy. Several barriers exist between dosing a drug and the target, which include drug permeation across epithelial membranes, metabolism, transport into and out of tissues, and plasma protein binding. The roles of drug metabolizing enzymes and drug transporters in ADME/PK of phytochemicals and their interaction with the naturally occurring small molecules are the subject of three contributions by Wu et al. [19], L. Li et al. [20], and Y. Li et al. [21]. These review articles may help us logically deal with the drug metabolizing enzymes or transporters in the context of the ADME study of herbal medicine. Cytochromes P450 (CYPs) constitute a superfamily of heme-thiolate proteins that catalyze the phase I oxidation reaction on many endogenous and xenobiotic chemicals. In humans, vast majority of oxidative metabolism of clinically used drugs are attributed to one or more CYP enzymes. The USA FDA has typically expected for the new chemical entity a statement concerning its interactions with CYPs. Wu et al. summarize the current knowledge on the relationship of phytochemicals from several commonly used medicinal herbs to human CYPs, which include 31 substrates, 58 inhibitors, and 21 inducers of specific CYP enzymes. UDP-
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glucuronosyltransferases (UGTs) comprise a superfamily of proteins that catalyze the phase II glucuronidation reaction on a wide range of endogenous and xenobiotic chemicals, which are involved in inactivation and elimination of the target compounds. Many phytochemicals are good substrates of UGTs. L. Li et al. present glucuronidation reactions of flavonoids, as well as those of many other classes of phytochemicals, and discuss the potential of several botanical products to affect UGTs. In addition, a variety of transporters in ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies have been cloned and the functional analyses have suggested their significant roles in drug ADME/PK. Y. Li et al. described the importance of the ABC and SLC transporters in the ADME/PK of phytochemicals and the transporter-phytochemical interactions. Besides these host drug metabolizing enzymes and transporters, investigation into ADME/PK of herbal compounds should be accompanied by an appreciation of the commensal colonic microflora [22]. As described by Yu et al. [18], combinatorial metabolism of saponins, i.e., deglycosylation of the glycosides by the colonic microflora and the subsequent metabolism of the microbially released aglycones by the host, represent an important biotransformation process for the phytochemicals. Although herb-drug interactions appear to be less frequent and less serious than interactions between synthetic drugs, it primarily reflects a weaker pharmacological profile for herbal medicines as compared with their synthetic counterparts. It also reflects more likely underrecognition, under-reporting, and less research [23]. Many herb-drug interactions involve inhibition or induction of drug-metabolizing enzymes and/or drug transporters as mechanistic basis. Accordingly, in vitro studies are often implemented as a cost-effective technique for assessing potential herb-drug interactions. However, in vivo studies do not necessarily agree with the in vitro findings. The clinical study is essential for better evaluation of herb-drug interaction potential [24], which should also include the major circulating metabolites in the in vivo assessment of the interactions [25]. The contribution by He et al. updates the knowledge on herb-drug interactions with an emphasis of the mechanistic and clinical consideration [26]. Like synthetic drugs, the metabolism-induced adverse effect/toxicity should be assessed with herbal medicines using the mechanism-based approach. Complex chemical nature of herbal medicine usually makes the study of toxic metabolites more difficult and challenging as compared with the study of synthetic drug-induced toxicity. Using hepatotoxicity induced by metabolic activation of pyrrolizidine alkaloids and nephrotoxicity by aristolochic acid as examples, Ma et al. present significance and contribution of the metabolism study in elucidation of toxic mechanisms, identification of biomarkers for the diagnosis and assessment of toxicity, and reduction and prevention of toxicity for herbal medicines [27]. In addition, Liu et al. present the application of nanotechnology in development of herbal medicines and the associated ADME/PK research [28]. Given the impressive degree of acceptance of herbal medicines, investigation into their safety and efficacy remains a necessary and fertile area of inquiry for ADME/PK scientists. Efforts have been made to bring rationality to this important component of current health care. The ADME/PK studies support making evidence-based decision about the value and use of herbal therapy. In this special issue of Current Drug Metabolism, we assembled a group of active and experienced researchers. They either provided their own research results [7-9] or surveyed the current research landscape of the field [10,13,18-21,26-28]. We hope that our collection will stimulate further discussion of and more research efforts on many important questions in ADME/PK of herbal medicines. ACKNOWLEDGEMENT This work was supported by the National Science Fund for Distinguished Young Scholars of China (Grant number 30925044), the National Science & Technology Major Project of China “Key New Drug Creation and Manufacturing Program” (Grant number 2009ZX09304-002), and the National Basic Research Program of China (Grant number 2012CB518403). The guest editor thanks the authors for submitting their interesting articles to Current Drug Metabolism and also thanks the reviewers and the editorial stuff of Bentham Science for their help and support. REFERENCES [1] [2] [3] [4] [5]
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Yu, K.; Chen, F.; Li, C. Absorption, disposition, and pharmacokinetics of saponins: what do we know and what do we need to know? Curr. Drug Metab., 2012, 13(5), 577-98. Wu, J-J.; Ai, C-Z.; Liu, Y.; Zhang, Y-Y.; Jiang, M.; Lu A-P.; Yang, L. Interactions between phytochemicals from traditional Chinese medicines and human cytochrome P450 enzymes. Curr. Drug Metab., 2012, 13(5), 599-614. Li, L.; Hu, H-H.; Xu, S-Y.; Zeng, S. Roles of UDP-glucuronosyltransferases in phytochemical metabolism of herbal medicines and the associated herb-drug interactions. Curr. Drug Metab., 2012, 13(5), 615-23. Li, Y.; Lu, J.; Paxton, J.W. The role of ABC and SLC transporters in the pharmacokinetics of dietary and herbal phytochemicals and their interactions with xenobiotics. Curr. Drug Metab., 2012, 13(5), 624-39. Possemiers, S.; Bolca, S.; Verstraete, W.; Heyerick, A. The intestinal microbiome: a separate organ inside the body with the metabolic potential to influence the bioactivity of botanicals. Fitoterapia, 2011, 82(1), 53-66. Ernst, E. Herb-drug interactions: potentially important but woefully under-researched. Eur. J. Clin. Pharmacol., 2000, 56(8), 523-524. Gurley, B.J.; Gardner, S.F.; Hubbard, M.A.; Williams D.K.; Gentry, W.B.; Cui Y-Y.; Ang, C.Y.W. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin. Pharmacol. Ther., 2002, 72(3), 276-287. Yeung, C.K.; Fujioka, Y.; Hachad, H.; Levy, R.H.; Isoherranen, N. Are circulating metabolites important in drug-drug interactions? quantitative analysis of risk prediction on inhibitory potency. Clin. Pharmacol. Ther., 2011, 89(1), 105-113. Chen, X.-W.; Sneed, K.B.; Pan, S.-Y.; Cao, C.; Kanwar, J.R.; Chew, H.; Zhou, S.-F. Herb-drug interactions and mechanistic and clinical considerations. Curr. Drug Metab., 2012, 13(5), 640-51. Ma, B.; Li, N.; Lin, G. Drug metabolic study to the safe use of Chinese herbal medicines. Curr. Drug Metab., 2012, 13(5), 652-8. Liu, C-X.; Si, D-Y.; Xiao, X-F.; He X.; Li Y-Z. Drug metabolism and pharmacokinetics of nano-drugs from Chinese medicines and natural products. Curr. Drug Metab., 2012, 13(5), 659-66.
Professor Chuan Li Laboratory for DMPK Research of Herbal Medicines Shanghai Institute of Materia Medica Chinese Academy of Sciences 501 Haike Road, Zhangjiang Hi-Tech Park Shanghai 201203 China Tel/Fax: +86-21-50803106 E-mail:
[email protected]
Current Drug Metabolism Volume 13, Number 5, June 2012
Contents Hot Topic
Absorption, Disposition, and Pharmacokinetics of Herbal Medicines: What and How? Guest Editor: Chuan Li Editorial
491
Intestinal Absorption and Presystemic Elimination of Various Chemical Constituents Present in GBE50 Extract, a Standardized Extract of Ginkgo biloba Leaves Li Li, Yuansheng Zhao, Feifei Du, Junling Yang, Fang Xu, Wei Niu, Yaohui Ren and Chuan Li
494
Metabolite Profiling and Pharmacokinetics of Herbal Compounds Following Oral Administration of a Cardiovascular Multi-herb Medicine (Qishen Yiqi Pills) in Rat Yufeng Zhang, Peiying Shi, Hong Yao, Qing Shao and Xiaohui Fan
510
Metabolic Conversion from Co-existing Ingredient Leading to Significant Systemic Exposure of Z-butylidenephthalide, a Minor Ingredient in Chuanxiong Rhizoma in Rat Ru Yan, Nga Ling Ko, Bin Ma, Yun Kau Tam and Ge Lin
524
Metabolite Profiling and Characterization for Medicinal Herbal Remedies Min Yang, Chunru Cheng, Junling Yang and De-an Guo
535
Pharmacokinetics-Pharmacology Disconnection of Herbal Medicines and its Potential Solutions with Cellular Pharmacokinetic-Pharmacodynamic Strategy Jingwei Zhang, Fang Zhou, Meng Lu, Wei Ji, Fang Niu, Weibin Zha, Xiaolan Wu, Haiping Hao and Guangji Wang
558
Absorption, Disposition, and Pharmacokinetics of Saponins from Chinese Medicinal Herbs: What Do We Know and What Do We Need to Know More? Ke Yu, Feng Chen and Chuan Li
577
Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes Jing-Jing Wu, Chun-Zhi Ai, Yong Liu, Yan-Yan Zhang, Miao Jiang, Xu-Ran Fan, Ai-Ping Lv and Ling Yang
599
Roles of UDP-Glucuronosyltransferases in Phytochemical Metabolism of Herbal Medicines and the Associated Herb-Drug Interactions Li Li, Haihong Hu, Siyun Xu, Quan Zhou and Su Zeng
615
The Role of ABC and SLC Transporters in the Pharmacokinetics of Dietary and Herbal Phytochemicals and their Interactions with Xenobiotics Yan Li, Jun Lu and James W. Paxton
624
Herb-Drug Interactions and Mechanistic and Clinical Considerations Xiao-Wu Chen, Kevin B. Sneed, Si-Yuan Pan, Chuanhai Cao, Jagat R. Kanwar, Helen Chew and Shu-Feng Zhou
640
Importance of Metabolic Activation Study to the Safe Use of Chinese Herbal Medicines Bin Ma, Na Li and Ge Lin
652
Drug Metabolism and Pharmacokinetics of Nanodrugs from Chinese Medicines and Natural Products Chang-Xiao Liu, Duan-Yun Si, Xue-Feng Xiao, Xin He and Ya-Zhuo Li
659
General Articles Measurement of CYP1A2 Activity: A Focus on Caffeine as a Probe Vidya Perera, Annette S. Gross and Andrew J. McLachlan
667
Characterization of Single Nucleotide Polymorphisms of Cytochrome P450 in an Australian Deceased Sample Jennifer L. Pilgrim, Yarimar Ruiz, Alejandro Gesteira, Raquel Cruz, Dimitri Gerostamoulos, Angel Carracedo and Olaf H. Drummer
679
