Preclinical pharmacokinetics-related pharmacological effects of orally administered polysaccharides from traditional Chinese medicines: A review.

Polysaccharides (TCMPs) derived from traditional Chinese medicines (TCMs), such as Ganoderma lucidum, Astragalus membranaceus, Lycium barbarum, and Panax ginseng, are considered to be the main active constituents in TCMs. However, the significant pharmacological effects of orally administered TCMPs do not align well with their poor pharmacokinetics. This article aims to review the literature published mainly from 2010 to 2022, focusing on the relationship between pharmacokinetics and pharmacological effects. It has been found that unabsorbed TCMPs can exert local pharmacological effects in the gut, including anti-inflammation, anti-oxidation, regulation of intestinal flora, modulation of intestinal immunity, and maintenance of intestinal barrier integrity. Unabsorbed TCMPs can also produce systemic pharmacological effects, such as anti-tumor activity and immune system modulation, by regulating intestinal flora and immunity. Conversely, some TCMPs can be absorbed and distributed to various tissues, especially the liver, where they exhibit tissue-protecting effects against inflammation and oxidative stress-induced damage and improve glucose and lipid metabolism. In future studies, it is important to improve quality control and experimental design. Furthermore, research on enhancing the oral bioavailability of TCMPs, exploring the activity of TCMP metabolites, investigating pharmacokinetic interactions between TCMPs and oral drugs, and developing oral drug delivery systems using TCMPs holds great significance.

Tissue distribution and integrated pharmacokinetic properties of major effective constituents of oral Gegen-Qinlian decoction in mice.

Gegen-Qinlian decoction (GQD) is a classic traditional Chinese medicine (TCM) formula. GQD is effective against colon or liver-related diseases including ulcerative colitis, non-alcoholic fatty liver, and type 2 diabetes. In this study, a liquid chromatography-tandem mass spectrometry method was developed, validated, and then applied to reveal the tissue distribution and integrated pharmacokinetic properties of major effective constituents of oral GQD in mice. The established method was quick, sensitive, and accurate enough to analyze GQD constituents in plasma and tissue homogenate samples quantitatively. According to their concentrations in the portal vein, systemic circulation, liver and colon samples of the mice after oral administration of GQD, the concentration-time curves of the constituents were respectively plotted. The results showed that daidzein, baicalin, and baicalein had relatively high exposure levels in the livers, while puerarin, berberine, epiberberine, coptisine, palmatine, jatrorrhizine, magnoflorine, glycyrrhizic acid, and glycyrrhetinic acid were enriched in the colons. Given that these constituents have significant biological activity, they could be regarded as the major effective constituents of GQD in treating colon or liver-related diseases, respectively. In addition, the integrated pharmacokinetic properties of GQD were studied. The GQD "integrated constituent" reached peak concentration at 4.0 h in the portal vein, the systemic circulation, the livers, and the colons, with half-lives of 1.5-4.1 h and mean retention time of 4.5-6.3 h, respectively. Furthermore, the concentration of the GQD "integrated constituent" in the colons was approximately 10 times higher than that in the livers, both of which were much higher than that in the systemic circulation, indicating its accumulation in these tissues, especially in the colons. In conclusion, the tissue distribution and integrated pharmacokinetic properties of oral GQD were revealed in the study. The results of the tissue distribution study would contribute to identifying the major target tissues and effective constituents of GQD, while the results of the integrated pharmacokinetic study would help to explain the pharmacokinetic properties of oral GQD as a whole.

Natural Nano-Drug Delivery System in Coptidis Rhizoma Extract with Modified Berberine Hydrochloride Pharmacokinetics.

PURPOSE: This study aimed to evaluate the pharmaceutical and pharmacokinetic effects of the natural nanoparticles (Nnps) isolated from Coptidis Rhizoma extract on berberine hydrochloride (BBR) and systematically explore the related mechanisms. METHODS: Firstly, Nnps were isolated from Coptidis Rhizoma extract and then an Nnps-BBR complex was prepared. After qualitative and quantitative analysis in terms of size, Zeta potential, morphology, and composition of the Nnps and the Nnps-BBR complex, the effects of the Nnps on the crystallization of BBR were characterized. The effects of the Nnps on the solubility and dissolution of BBR were then evaluated. In addition, the effects of the Nnps on BBR in terms of cellular uptake, transmembrane transport, metabolic stability, and pharmacokinetics in mice were studied. RESULTS: The Nnps had an average size of 166.6 ± 1.3 nm and Zeta potential of -12.5 ± 0.2 mV. The Nnps were formed by denaturation of co-existing plant proteins with molecular weight < 30 kDa. The Nnps adsorbed or dispersed BBR, thereby promoting BBR transformation from crystal to amorphous form and improving its solubility and dissolution. The Nnps carried and promoted BBR uptake by human colonic adenocarcinoma (Caco-2) cells via caveolae-mediated endocytosis, reducing P-gp-mediated efflux of BBR in mice gut sacs and Madin-Darby canine kidney cells stably expressing the transporter P-gp (MDCK-MDR1) cells. Moreover, the Nnps improved BBR metabolic stability in mouse intestinal S9, promoting BBR intestinal absorption in mice, as shown by increased peak BBR concentration (Cmax, 1182.3 vs 310.2 ng/mL) and exposure level (AUC0-12 h, 2842.8 vs 1447.0 ng·h/mL) in mouse portal vein. In addition, the Nnps increased BBR exposure level in mouse livers (95,443.2 vs 43,586.2 ng·h/g liver). CONCLUSION: The proteinaceous nanoparticles isolated from Coptidis Rhizoma extract can form a natural nano-drug delivery system with BBR, thereby significantly improving the pharmacokinetics of oral BBR.

Constituents, Pharmacokinetics, and Pharmacology of Gegen-Qinlian Decoction.

Gegen-Qinlian decoction (GQD) is a classic traditional Chinese medicine (TCM) formula. It is composed of four TCMs, including Puerariae Lobatae Radix, Scutellariae Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma Praeparata cum Melle. GQD is traditionally and clinically used to treat both the "external and internal symptoms" of diarrhea with fever. In this review, key words related to GQD were searched in the Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), and other databases. Literature published mainly from 2000 to 2020 was screened and summarized. The main constituents of GQD could be classified into eight groups according to their structures: flavonoid C-glycosides, flavonoid O-glucuronides, benzylisoquinoline alkaloids, free flavonoids, flavonoid O-glycosides, coumarins, triterpenoid saponins, and others. The parent constituents of GQD that enter circulation mainly include puerarin and daidzein from Puerariae Lobatae Radix, baicalin and wogonoside from Scutellariae Radix, berberine and magnoflorine from Coptidis Rhizoma, as well as glycyrrhetinic acid and glycyrrhizic acid from Glycyrrhizae Radix et Rhizoma Praeparata cum Melle. GQD is effective against inflammatory intestinal diseases, including diarrhea, ulcerative colitis, and intestinal adverse reactions caused by chemotherapeutic agents. Moreover, GQD has significant effects on metabolic diseases, such as nonalcoholic fatty liver and type 2 diabetes. Furthermore, GQD can be used to treat lung injury. In brief, the main constituents, the pharmacokinetic and pharmacological profiles of GQD were summarized in this review. In addition, several issues of GQD including effective constituents, interactions between the constituents, pharmacokinetics, interaction potential with drugs and pharmacological effects were discussed, and related future researches were prospected in this review.

Pharmacokinetic incompatibility of the Huanglian-Gancao herb pair.

BACKGROUND: Pharmacokinetic interaction is one of the most important indices for the evaluation of the compatibility of herbal medicines. Both Gancao (Glycyrrhizae Radix et Rhizoma) and Huanglian (Coptidis Rhizoma) are commonly used traditional Chinese medicines (TCMs). In this study, the influence of Gancao on the pharmacokinetics of Huanglian was systematically studied by using berberine as a pharmacokinetic marker. METHODS: Extracts of the herbal pieces of Huanglian and the herb pair (Huanglian plus Gancao) were prepared with boiling water. The concentration of berberine in the samples was analyzed using liquid chromatography-mass spectrometry. The total amounts of berberine in all extract samples were compared. Comparative pharmacokinetic studies of Huanglian and the herb pair were conducted in ICR mice. In vitro berberine absorption and efflux were studied using mice gut sacs. The equilibrium solubility of berberine in the extracts was determined. The in vitro dissolution of berberine was comparatively studied using a rotating basket method. RESULTS: Gancao significantly reduced berberine exposure in the portal circulation (425.8 ng·h/mL vs. 270.4 ng·h/mL) and the liver (29,500.8 ng·h/mL vs. 15,422.4 ng·h/mL) of the mice. In addition, Gancao decreased the peak concentration (Cmax) of berberine in the portal circulation (104.3 ng·h/mL vs. 76.5 ng·h/mL) and liver (4926.1 ng·h/mL vs. 2642.8 ng·h/mL) of mice. Significant influences of Gancao on the amount of berberine extracted (32% reduction), the solubility of berberine (34.7% compared with the control group), and dissolution (88.7% vs. 66.1% at 15 min in acid buffer and 68% vs. 51.8% at 15 min in phosphate buffer) were also revealed. Comparative pharmacokinetic studies in ICR mice indicated that the formation of sediment was unfavorable in terms of berberine absorption (345.3 ng·h/mL vs. 119.8 ng·h/mL). CONCLUSIONS: Gancao was able to reduce intestinal absorption and in vivo exposure of berberine in Huanglian via the formation of sediment, which caused reductions in the extracted amount, solubility, and dissolution of berberine.

Synergistic Mechanisms of Constituents in Herbal Extracts during Intestinal Absorption: Focus on Natural Occurring Nanoparticles.

The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer herbal extracts are sometimes less effective. Pharmacological loss of purified constituents is closely associated with their significantly reduced intestinal absorption after oral administration. In this review, pharmacokinetic synergies among constituents in herbal extracts during intestinal absorption were systematically summarized to broaden the general understanding of the pharmaceutical nature of herbal medicines. Briefly, some coexisting constituents including plant-produced primary and secondary metabolites, promote the intestinal absorption of active constituents by improving solubility, inhibiting first-pass elimination mediated by drug-metabolizing enzymes or drug transporters, increasing the membrane permeability of enterocytes, and reversibly opening the paracellular tight junction between enterocytes. Moreover, some coexisting constituents change the forms of bioactive constituents via mechanisms including the formation of natural nanoparticles. This review will focus on explaining this new synergistic mechanism. Thus, herbal extracts can be considered mixtures of bioactive compounds and pharmacokinetic synergists. This review may provide ideas and strategies for further research and development of herbal medicines.

Pharmacokinetics, bioavailability and tissue distribution studies of rhodojaponin III in mice using QTRAP LC-MS/MS.

Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.

Zhujie Hewei Granules Ameliorated Reflux Esophagitis in Rats.

BACKGROUND: Gastroesophageal reflux disease (GERDs) is a common chronic digestive system disease, in which the symptoms of reflux esophagitis (RE) seriously affect the quality of life. AIMS: We aimed to study the therapeutic effect of Zhujie Hewei granules (ZHG) on reflux esophagitis in model rats. MATERIALS AND METHODS: A rat model of RE was established with the steps of half pylorus ligation, cardiotomy, and hydrochloric acid perfusion. The rats in treatment groups were orally administered with 1.30, 2.60, or 5.20 g/kg ZHG once daily for 28 days. Histopathological changes of the esophagus were observed with hematoxylin-eosin staining. The content of total bilirubin and pH in gastric juice was determined. Esophageal mucosal injury was assessed by macroscopic observation scores, mucosal injury index scores, and esophageal inflammation scores. The levels of gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) in serum were evaluated by using ELISA kits. RESULTS: After treatment with ZHG, the body weight of RE rats tended to increase drastically, the macroscopic observation scores of the esophagus mucous membrane decreased (P < 0.05), the mucosal injury index scores decreased (P < 0.05), the gastric pH values increased (P < 0.05), and the levels of serum MTL and VIP decreased (P < 0.05). In addition, the high dose of the ZHG-treated group showed lower serum GAS (P < 0.05), while the high and middle doses of the ZHG-treated groups showed lower esophageal inflammation scores (P < 0.05). CONCLUSIONS: ZHG was effective in treating RE in rats due using mechanisms including improving the pH value of gastric contents, decreasing the gastrointestinal hormones (including GAS, MTL, and VIP), and improving the inflammatory damage.

Pharmacokinetic mechanisms underlying the detoxification effect of Glycyrrhizae Radix et Rhizoma (Gancao): drug metabolizing enzymes, transporters, and beyond.

INTRODUCTION: Glycyrrhizae Radix et Rhizoma (Gancao in Chinese) is the most frequently used traditional Chinese medicine (TCM) owing to its various pharmacological effects and, more importantly, the synergistic effects that enhance the efficacy and reduce the toxicity of other TCMs. Areas covered: We reviewed publications, predominantly between 1990 and 2018, that examined pharmacokinetic interactions between Gancao and other TCMs, or the bioactive constituents of these TCMs. This review focuses on the underlying mechanisms and the components responsible for the pharmacokinetic modulation by Gancao. Expert opinion: In general, the pharmacokinetic effects of Gancao are a result of its constituents such as macromolecules, like proteins, and small molecules, such as saponins and flavonoids. The mechanisms are related to formation of complexes and the influence of these on drug solubility, permeability, distribution, and metabolism. The detoxification effect of a single dose of Gancao is mainly mediated by the suppression of the intestinal absorption of toxic constituents of the co-administered TCMs and is attributable to constituents that form complexes with the toxic compounds and cause them to sediment. In contrast, the detoxification effects of repeated doses of Gancao are mediated mainly via the induction of drug metabolizing enzymes and efflux transporters.

A Compositive Strategy to Study the Pharmacokinetics of TCMs: Taking Coptidis Rhizoma, and Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma as Examples.

Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in CoptidisRhizoma (CRE), and berberine in CoptidisRhizoma-GlycyrrhizaeRadix etRhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.

Huangqi Decoction Alleviates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis by Reversing Disordered Bile Acid and Glutathione Homeostasis in Mice.

Intrahepatic cholestasis is a serious symptom of liver disorders with limited therapies. In this study, we investigated the efficacy of Huangqi decoction (HQD), a two-herb classic traditional Chinese medicine (TCM), in the treatment of alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. HQD treatment ameliorated impaired hepatic function and tissue damage. A metabolomics study revealed that the endogenous metabolites significantly affected by HQD were related to bile acid (BA) biosynthesis and glutathione metabolism pathways. HQD treatment decreased the intrahepatic accumulation of cytotoxic BAs, normalized serum BA levels, and increased biliary and urinary BA excretion. Additionally, HQD restored the hepatic glutathione content and suppressed reactive oxygen species (ROS) in cholestatic mice. Protein and gene analysis revealed that HQD increased the expression of the hepatic metabolizing enzymes cytochrome P450 (CYP) 2B10 and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), as well as multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4, which play crucial roles in BA homeostasis. Further, HQD increased the protein expression of glutamate-cysteine ligase, which is involved in the synthesis of glutathione. Importantly, HQD increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). In conclusion, HQD protects against intrahepatic cholestasis by reversing the disordered homeostasis of BAs and glutathione.

Pharmacokinetic herb-drug interactions with traditional Chinese medicine: progress, causes of conflicting results and suggestions for future research.

Traditional Chinese medicine (TCM) has a long history of medical use in China and is still used worldwide. Unexpected herb-drug interactions (HDIs) may lead to adverse drug reactions or loss of therapeutic efficacy of the victim drug. Here, based on searches of Medline, EBSCO, Science Direct and Web of Science using various keywords, we summarize the TCM-derived pharmacokinetic HDIs that were reported from 1990 to 2015 and discuss the underlying mechanisms. In general, many pre-clinical and clinical pharmacokinetic HDIs have been reported. Our searches show that TCMs cause pharmacokinetic interactions with therapeutic drugs mainly by inhibiting or inducing drug-metabolizing enzymes and transporters. However, most of the interactions result from a small number of prescription medications and the actual potential for harm is low. Moreover, such HDIs can be avoided by discontinuing the TCMs. Despite the extensive number of reports on TCM-derived HDIs, the findings are frequently conflicting and can be confusing. The causes of the conflicts vary, but we classified them into three basic categories as follows: (1) complicated nature and poor quality control of TCMs, (2) different responses of various test systems to TCM exposure and (3) diverse study designs. Accordingly, we propose rational study designs for future HDI research. We also propose that a specific authoritative guide be established that provides recommendations for HDI studies. This review provides insights into the progress and challenges in TCM-derived pharmacokinetic HDI research.

Naturally occurring proteinaceous nanoparticles in Coptidis Rhizoma extract act as concentration-dependent carriers that facilitate berberine absorption.

Pharmacological activities of some natural products diminish and even disappear after purification. In this study, we explored the mechanisms underlying the decrease of acute oral toxicity of Coptidis Rhizoma extract after purification. The water solubility, in vitro absorption, and plasma exposure of berberine (the major active compound) in the Coptidis Rhizoma extract were much better than those of pure berberine. Scanning electron microscopy, laser scanning confocal microscopy (LSCM), and dynamic light scattering experiments confirmed that nanoparticles attached to very fine precipitates existed in the aqueous extract solution. The LSCM experiment showed that the precipitates were absorbed with the particles by the mouse intestine. High-speed centrifugation of the extract could not remove the nanoparticles and did not influence plasma exposure or acute oral toxicity. However, after extract dilution, the attached precipitates vanished, although the nanoparticles were preserved, and there were no differences in the acute oral toxicity and plasma exposure between the extract and pure berberine. The nanoparticles were then purified and identified as proteinaceous. Furthermore, they could absorb co-dissolved berberine. Our results indicate that naturally occurring proteinaceous nanoparticles in Coptidis Rhizoma extract act as concentration-dependent carriers that facilitate berberine absorption. These findings should inspire related studies in other natural products.

Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats.

In Chinese medicine, Xiexin decoction (XXD) has been used for the clinical treatment of diabetes for at least 1700 years. The present study was conducted to investigate the effective ingredients of XXD and their molecular mechanisms of antidiabetic nephropathy in rats. Rats with diabetes induced by high-fat diet and streptozotocin were treated with XXD extract for 12 weeks. XXD significantly improved the glucolipid metabolism disorder, attenuated albuminuria and renal pathological changes, reduced renal advanced glycation end-products, inhibited receptor for advanced glycation end-product and inflammation factors expression, suppressed renal nuclear factor- κ B pathway activity, and downregulated renal transforming growth factor- ß 1. The concentrations of multiple components in plasma from XXD were determined by liquid chromatography and tandem mass spectrometry. Pharmacokinetic/pharmacodynamic analysis using partial least square regression revealed that 8 ingredients of XXD were responsible for renal protective effects via actions on multiple molecular targets. Our study suggests that the renal protective role of XXD with multiple effective ingredients involves inhibition of inflammation through downregulation of the nuclear factor- κ B pathway, reducing renal advanced glycation end-products and receptor for advanced glycation end-product in diabetic rats.

Pharmacokinetic properties, potential herb-drug interactions and acute toxicity of oral Rhizoma coptidis alkaloids.

INTRODUCTION: Rhizoma coptidis shows various pharmacological activities attributed to its alkaloid constituents. To guide the pharmacological studies, the candidate drug research and development and the clinic applications of these compounds, a review on their pharmacokinetic behavior and toxicity should be beneficial. AREAS COVERED: This article looks at the pharmacokinetic properties and potential herb-drug interactions found with Rhizoma coptidis alkaloids. Furthermore, the article also reviews the acute toxicity of these alkaloids. EXPERT OPINION: Generally, the systemic exposures of the alkaloids are extremely low after oral administration. The alkaloids may present their systemic activities via generated metabolites and/or the tissue distributed alkaloids themselves, or by modulating effectors in the gut. The drug transporters and drug-metabolizing enzymes involved in the in vivo process, the modulatory effects on both P-glycoprotein and cytochrome P450 isoenzymes and the acute toxicity of the alkaloids were all well documented. However, first, since very significant difference exists between the blood and tissue exposure, to find suitable pharmacokinetic markers of the alkaloids in blood may be challenging but necessary. Second, the dose-systemic exposure-response relationships of the alkaloids should also be determined. Third, in order to improve the oral bioavailability and efficacy, it is important to design derivatives or formulations of the alkaloids with better pharmacokinetic features.

Increased systemic exposure to rhizoma coptidis alkaloids in lipopolysaccharide-pretreated rats attributable to enhanced intestinal absorption.

Rhizoma coptidis is a rhizome commonly used in traditional Chinese medicine. After oral administration of rhizoma coptidis extract, the plasma concentrations of its effective alkaloid constituents are so low that their systemic therapeutic actions cannot be explained. This study aimed to investigate the influence of lipopolysaccharide (LPS) on the pharmacokinetics of the rhizoma coptidis alkaloids. Pharmacokinetic experiments were performed with rats; both in vitro absorption and efflux experiments were carried out with everted rat gut sacs, whereas in vitro metabolism experiments were conducted with rat liver microsomes and intestinal S9 fractions. Mucosal changes were evaluated with light microscopy and transmission electron microscopy. The results showed that, in rat plasma, LPS pretreatment increased systemic alkaloid exposure. LPS pretreatment increased the in vitro absorption of the alkaloids and decreased their efflux. The efflux of vinblastine and rhodamine 123, P-glycoprotein substrates, also was decreased. The absorption of fluorescein isothiocyanate-labeled dextran (average molecular mass, 4 kDa), a gut paracellular permeability probe, was not influenced. Obvious damage was observed in the mucosa, but the tight junctions between epithelial cells remained intact. Intestinal, rather than hepatic, alkaloid metabolism was decreased. These findings indicated that LPS pretreatment increased systemic exposure to the alkaloids through enhancement of their absorption, which was related to decreased intestinal efflux and metabolism. The results add to the understanding of why rhizoma coptidis is active despite the low plasma concentrations of the rhizoma coptidis alkaloids measured in normal subjects and experimental animals.

Lipopolysaccharide increased the acute toxicity of the Rhizoma coptidis extract in mice by increasing the systemic exposure to Rhizoma coptidis alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma coptidis is used as an antidysenteric in clinics in China. However, patients suffering from dysentery are susceptible to the acute toxicity of Rhizoma coptidis. The current study investigates the effects of lipopolysaccharide (LPS), which are a key pathogenic factor in dysentery, on the acute toxicity of a Rhizoma coptidis extract in mice; possible mechanisms are proposed. MATERIALS AND METHODS: Acute toxicity and pharmacokinetic experiments in mice were conducted. The plasma concentration of Rhizoma coptidis alkaloids in mice was determined using liquid chromatography/tandem mass spectrometry. The activity of acetylcholinesterase (AChE) in the tissue homogenate was determined using an AChE determination kit. RESULTS: Pretreatment with LPS for 16 h increased the acute toxicity of the oral Rhizoma coptidis extract. Systemic exposure to Rhizoma coptidis alkaloids was also increased by LPS pretreatment. Neostigmine significantly increased whereas pyraloxime methylchloride reduced the acute toxicity of the Rhizoma coptidis extract. LPS pretreatment alone showed no significant effect on the activity of thoracoabdominal diaphragm AChE. However, it enhanced the inhibitory effect of the Rhizoma coptidis extract. LPS pretreatment did not affect the acute toxicity of various dosages of tail vein-injected berberine. CONCLUSIONS: LPS increased the acute toxicity of the oral Rhizoma coptidis extract in mice by increasing the systemic exposure to the Rhizoma coptidis alkaloids.

Influences of Fructus evodiae pretreatment on the pharmacokinetics of Rhizoma coptidis alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma coptidis is a traditional Chinese medicine with pharmacological properties. It is usually prescribed with Fructus evodiae as traditional Chinese medicine (TCM) formulas. Here we report the influences of Fructus evodiae on the pharmacokinetics of the Rhizoma coptidis alkaloids and propose possible mechanisms. MATERIALS AND METHODS: Pharmacokinetic experiments were performed in rats. In vitro absorption experiments were performed in everted rat gut sacs, while in vitro metabolism experiments and determination of hepatic UDP-glucuronosyltransferase (UGT) 1A1 mRNA expression were performed in rat liver microsomes. RESULTS: Pretreatment with Fructus evodiae extract for two weeks decreased the systemic exposure of the Rhizoma coptidis alkaloids. This effect was not due to inhibition of absorption or enhanced hepatic phase I metabolism of the Rhizoma coptidis alkaloids. However, Fructus evodiae pretreatment enhanced both the activity and expression of hepatic UGT1A1. CONCLUSIONS: The results showed that Fructus evodiae pretreatment decreased the systemic exposure of the Rhizoma coptidis alkaloids by inducing hepatic UGT1A1.

Identification of the toxic constituents in Rhizoma Coptidis.

AIM OF THE STUDY: Rhizoma Coptidis (Huanglian) is a widely used Traditional Chinese Medicine. However, it causes human as well as animal toxicities. In this study, we aimed to ascertain the toxic constituents in Rhizoma Coptidis. MATERIALS AND METHODS: The acute toxicity of both the total extract and the alkaloid-rich extract of Rhizoma Coptidis were tested in mice. The dose related tissue concentration of the Rhizoma Coptidis alkaloids in mice was determined using high performance liquid chromatography with ultraviolet detection. The influence of phenobarbital sodium [a non-selective hepatic enzyme (P450) inducer] on the acute toxicity of Rhizoma Coptidis as well as the tissue concentration of the alkaloids was investigated. The cytotoxicity of the Rhizoma Coptidis alkaloids was tested in six cell lines using the MTT assay. RESULTS: The median acute oral lethal dose of the total extract of Rhizoma Coptidis was 2.95g/kg in mice. The alkaloid-rich extract was much more toxic than the total extract of Rhizoma Coptidis. Four Rhizoma Coptidis alkaloids were detected in brain, heart, and lung tissues of mice that received the oral total extract of Rhizoma Coptidis. Tissue concentration increased nonlinearly with higher doses. Phenobarbital sodium decreased the tissue concentration of every alkaloid as well as the toxicity of Rhizoma Coptidis. All alkaloids, especially berberine, showed dose and time dependent cytotoxicity. CONCLUSIONS: The toxic constituents of Rhizoma Coptidis were the alkaloids, mainly berberine.

Effective constituents in Xiexin Decoction for anti-inflammation.

AIM OF THE STUDY: To ascertain the effective constituents in Xiexin Decoction for anti-inflammation and the interactions of these constituents at the pharmacodynamic level. MATERIALS AND METHODS: Rats were administered oral Xiexin Decoction 1h before intraperitoneal lipopolysaccharide. Nitric oxide production and Xiexin Decoction constituents in venous serum samples were quantified and the correlation between nitric oxide production and each constituent in serum was calculated. Raw264.7 cells were stimulated with lipopolysaccharide and one or more Xiexin Decoction constituents; cell viability and nitric oxide production was quantified. RESULTS: Xiexin Decoction significantly decreased nitric oxide production in vivo, which correlated well with rhein, baicalin, emodin and aloe-emodin. All the typical constituents of Xiexin Decoction, with the exception of physcione and chrysophanol, dose-dependently inhibited nitric oxide production in vitro. In an orthogonal designed in vitro study, rhein was the most powerful constituent, followed by baicalin then berberine and no synergy was found among these constituents. CONCLUSIONS: Rhein was the most effective anti-inflammatory constituent in Xiexin Decoction followed by baicalin; no synergy was observed between rhein, baicalin and berberine at the pharmacodynamic level in vitro.