Garsubelone A, the First Dimeric Polycyclic Polyprenylated Acylphloroglucinols with Complicated Heptacyclic Architecture from Garcinia subelliptica.

Garsubelone A (1), the first dimeric polycyclic polyprenylated acylphloroglucinols type metabolite featuring a complicated 6/6/6/6/6/6/6 heptacyclic architecture containing 10 stereogenic centers, was isolated from Garcinia subelliptica. Biogenetically, this compound was constructed by the plausible monomeric precursor, garsubelone B (2) and secohyperforin, via a key Diels-Alder cycloaddition to form an unique 2-oxabicyclo[3.3.1]nonane core. Their structures and absolute configurations were determined by comprehensive spectroscopic and X-ray diffraction techniques. The cytotoxic activities of these isolates were also evaluated.

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.

Study of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration.

OBJECTIVE: To evaluate the pharmacokinetics and tissue distribution of liposomal brucine (LB) for dermal application. METHODS: Pharmacokinetics and tissue distribution were studied by in vivo animal testing. High performance liquid chromatography (HPLC) was used to detect the concentration of brucine in rats' skin, plasma and various tissues. RESULTS: After dermal administration, LB was absorbed rapidly in the skin and could be detected after 0.5 hours. After 36 hours, levels were too low to be detected. In plasma, levels were also too low to be detected after 36 hours. The concentration of LB reached 50% of the maximum in all tissues except the brain, peaking after 1.5 hours but still detectable after 12 hours. CONCLUSION: The concentration of LB was high in skin at the application site. LB was quickly absorbed into tissues through the blood circulation and widely distributed throughout the whole body. There was no obvious toxicity and LB did not readily accumulate in tissues and organs. It showed local potency but low overall systemic toxicity.

Preparation of liposomal brucine and its pharmaceutical/pharmacodynamic characterization.

AIM: To prepare a novel transdermal preparation of liposomal brucine (LB) and investigate its pharmaceutical/pharmacodynamic characterization. METHODS: LB was prepared by a modified ethanol-dripping method. Its drug encapsulation efficiency (EE), particle size, in vitro release, and skin permeation were studied. Furthermore, a safety evaluation and pharmacodynamic analysis of LB, including acute dermal toxicity, skin irritation, and analgesic and anti-inflammatory effects were investigated. RESULTS: the EE of LB was 72% and the mean particle size of the liposomes was 55.4 nm. The in vitro release profile indicated that less than 68% of the encapsulated brucine was released in 10 h. A skin permeation study showed that compared with the free brucine, LB exhibited higher cumulative drug permeation through the skin and lower drug accumulation in skin tissue, indicative of an obvious promotion of skin permeation with liposomal encapsulation. The acute dermal LD50 of LB was greater than 100 mg/kg (brucine content) and skin irritation tests revealed that LB had no irritation to both integrity and broken skin. A pharmacodynamic evaluation of LB was performed by xylene-induced mouse ear edema test and acetic acid-induced writhing test at the dosage of 1.5, 3, and 6 mg/kg, respectively. The results showed that anti-inflammatory activities and analgesic effects of brucine encapsulated were significantly higher than that of the free brucine (P<0.01). Moreover, LB maintained a remarkably longer antiinflammatory and analgesic duration. CONCLUSION: It can be proposed that LB prepared here could represent a safe, effective and promising transdermal formulation for analgesic and anti-inflammatory effects.