[Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats].

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats / 中国中药杂志

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

HPLC-MS/MS analysis of primary alkaloids in rat plasma after oral administration of "Nux vomica - Glycyrrhiza glabra decoction": A pharmacokinetic study.

ETHNOPHARMACOLOGICAL RELEVANCE: Decoction is the most common form of administering traditional Chinese medicine (TCM). During the preparation of decoction, the high temperature and complex chemical environment result in the formation of complex and multiple phases. The differences in drug components in different phases induce gastrointestinal absorption and physiological response. Nux vomica (Strychnos nux-vomica L) is a typical toxic TCM used in China, with remarkable pharmacological activity. In order to reduce its toxicity, nux vomica (NV) is often decocted with Glycyrrhiza glabra (GG) in clinic, and the detoxification mechanism has always been the focus of research interest. Most studies investigated the compatibility of NV-GG, but the in vivo behavior of individual constituents based on phase state has yet to be elucidated. AIM OF THE STUDY: To investigate the pharmacokinetic behavior of typical toxic components in different phase states of "NV-GG decoction" in rat plasma. MATERIALS AND METHODS: The sediment, suspension, colloid and true solution of "NV-GG decoction" was obtained via physical methods. The main components in different phase states were analyzed via reliable UFLC-Q-TOF-MS high-resolution mass spectrometry. A rapid and accurate HPLC-qqq-MS/MS method was established and validated for accurate determination of brucine and strychnine levels in plasma, followed by pharmacokinetic evaluation of different phase states of "NV-GG decoction" in rats. Kinetex F5 100A (50 mm × 3.0 mm, 2.6 µm) column was used for chromatographic separation. Aqueous solution containing acetonitrile and 0.1% formic acid was used as the mobile phase, followed by gradient elution at 0.4 mL/min. Mass spectra were detected by electrospray ionization (ESI) multiple reaction monitoring (MRM) in positive ion mode. RESULTS: Fifteen different alkaloids were detected in different phase states of "NV-GG decoction". Strychnine and brucine, which are toxic components with high content, were selected for quantitative analysis. The established UPLC-qqq-MS/MS method is accurate and reliable with a good linearity (R2 > 0.99) in the respective concentration range, satisfying the quantitative requirements. The pharmacokinetic parameters of different phase states of rats differed significantly after gavage. The deposition phase was the most prominent. The index components showed higher Cmax, AUC0 and Tmax, while the T1/2, MRT, V/F and CL/F were the smallest, with a relatively slow plasma clearance rate in rats. The true solution group showed the lowest Tmax and the fastest absorption. CONCLUSION: This method has been successfully utilized to study the pharmacokinetics of different phase states of "NV-GG decoction". Among the four phases, the deposition phase contributed to a large proportion of the in vivo kinetic behavior similar to that of sustained-release preparations, with slow absorption of toxic components and prolonged peak time. The pharmacokinetic parameters and plasma concentration-time curves of each phase can be used to study toxicity reduction of NV-GG and increase its biocompatibility.

Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. AIM OF THE STUDY: To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. MATERIALS AND METHODS: Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. RESULTS: All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. CONCLUSIONS: M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.

Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.

Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.

A novel UPLC-MS/MS method for simultaneous quantification of trigonelline, 4-hydroxyisoleucine, and diosgenin from Trigonella foenum-graecum extract: Application to pharmacokinetic study in healthy and type 2 diabetic rats.

Trigonelline (TR), 4-hydroxyisoleucine (4-HI), and diosgenin (DG) are the main bioactives of the purified standardized extract of the popular plant Trigonella foenum-graecum L. (TFG), and it has been proven effective for the treatment of various diseases. However, to the best of our knowledge, no study has investigated the pharmacokinetic parameters of purified standardized T. foenum-graecum extract in normal and diabetic Wistar rats. The present study has developed and validated a rapid, reliable, and sensitive simultaneous ultra-performance liquid chromatography MS method to estimate these bioactives. The chromatographic separation was achieved using methanol, acetonitrile, and 0.1% formic acid with the ideal gradient flow system on a BEH Shield RP 18 column. A positive electrospray ionization mode was selected to estimate m/z values of TR (138.14 > 94.63), 4-HI (148.19 > 74.08), and DG (415.54 > 271.33). The method was robust and reproducible over the linearity range of 60-5000, 6-5000, and 15-5000 ng/mL for TR, 4-HI, and DG, respectively. Using this novel validated method, we investigated the pharmacokinetic parameters of bioactives using Phoenix WinNonlin version 8.0 (Certera) in normal and diabetic rats. The assay was successfully applied for the estimation of pharmacokinetic parameters using noncompartmental analysis. This investigation shows that the absorption rate increased, whereas distribution and elimination processes slowed down in diabetic rats compared with normal rats.

Simultaneous determination of 11 alkaloids in rat plasma by LC-ESI-MS/MS and a pharmacokinetic study after oral administration of total alkaloids extracted from Naucleaofficinalis.

ETHNOPHARMACOLOGICAL RELEVANCE: Nauclea officinalis, a widely used Li medicine, has been used for the treatment of cold, fever, bronchitis, pneumonia, acute tonsillitis, and other ailments. Modern pharmacological studies have demonstrated that the most abundant and active components in N. officinalis are alkaloids, which possess various biological properties such as antibacterial and antitumor activities. AIM OF THE STUDY: To investigate the phytochemical profile of a selected group of alkaloids from the N. officinalis total alkaloids, and to determine the chemical profile of the alkaloids extracted from rat plasma. Further investigation was conducted to determine the pharmacokinetic behaviors of 11 selected major alkaloids, including pumiloside, naucleoxoside A, naucleoxoside B, nauclefine, angustidine, angustoline, (3S,19S)-3,14-dihydroangustoline,[α]D20: (-)191°, (3S,19R)-3,14-dihydroangustoline, [α]D20: (-) 294.7°, strictosamide, angustine, and 3,14-dihydroangustine. MATERIALS AND METHODS: N. officinalis total alkaloids were extracted with 79% ethanol and enriched with AB-8 macroporous resin. The phytochemical profile of alkaloids from the N. officinalis total alkaloids and the chemical profile of the alkaloids extracted from rat plasma were first analyzed by UPLC-Q-TOF-MS/MS. A simple, convenient, and sensitive LC-ESI-MS/MS method was subsequently developed and validated for the simultaneous determination of major active alkaloids in rat plasma after oral administration of N. officinalis total alkaloids. After addition of an internal standard (verapamil), plasma samples were pretreated first by protein precipitation with methanol and then underwent liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved using a Waters BEH C18 column (2.1 mm × 100 mm, 1.7 µm) at 30 °C, with gradient elution using a mobile phase consisting of 0.1% formic acid aqueous solution (A) and acetonitrile (B), a flow rate of 0.2 mL/min, and a total run time of 30 min. The detection was performed using an electrospray ionization triple quadrupole tandem mass spectrometer with multiple reaction monitoring and positive ionization mode. RESULTS: Based on the fragmentation patterns of 11 authentic alkaloids and previous reports, 55 alkaloids were identified or tentatively identified in the N. officinalis total alkaloids. Among them, 25 alkaloids were absorbed through the gastrointestinal tract in rats after administration of the N. officinalis total alkaloids. The 11 alkaloids were selected for quantitative analysis. The established quantitative method was fully validated and proved to be sensitive and specific. Satisfactory linearity of the 11 alkaloids obtained in the respective concentration ranges (r > 0.9931). The lower limits of quantification for strictosamide was 20.86 ng/ml, and the other ten alkaloids were all less than 4.47 ng/ml in rat plasma. The intra-and inter-day precision was less than 15% for all 11 alkaloids in terms of relative standard deviation, and the accuracies ranged from -11.4% to 11.1% in terms of relative error. Extraction recovery, matrix effect, and stability were within the required limits in rat plasma. CONCLUSION: The validated method was successfully applied to investigate the pharmacokinetics of the 11 alkaloids in rat plasma after oral administration of N. officinalis total alkaloids. Eleven alkaloids were rapidly absorbed to achieve a maximum plasma concentration with Tmax from 0.25 h to 1.5 h after oral administration. The pharmacokinetic parameters and plasma concentration-time profiles will prove valuable in pre-clinical and clinical investigations on the disposition of N. officinalis total alkaloids.

A review on the bioavailability, bio-efficacies and novel delivery systems for piperine.

As the major naturally occurring alkaloid in pepper with a pungent taste, piperine is known for its beneficial biological functions and therapeutic effects. In this work, the bioavailability and biological activities of piperine were presented and discussed. Novel delivery systems for enhancing the bioavailability of piperine were also reviewed. This study could provide a better understanding of the physiological and biochemical aspects of piperine to be further developed in the food and nutraceutical industries.

Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.

This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed in vitro activities of KACs were consistent with their cell signaling pathways predicted using the in silico network pharmacology approach. The pharmacokinetics of KACs were determined after i.v., i.p., and p.o. delivery using ATB extract and a mixture of four KACs in mice. Despite good solubilities and permeabilities, poor oral bioavailabilities were estimated for all KACs, mostly because of first-pass metabolism in the liver (for all KACs) and intestines (for matrine and fraxinellone). Multiple-dose PK studies showed 23.2-fold and 8.5-fold accumulation of dictamine and maackiain in the blood, respectively. Moreover, saliva levels of dictamine and matrine were found significantly higher than their blood levels. In conclusion, the systemic bioavailabilities of ATB-KACs were low, but significant levels of dictamine and matrine were found in saliva upon repeated oral administration. Significant salivary concentrations of matrine justified its possible use as a drug-monitoring tool to track patient compliance during chemoprevention trials.

Statistical optimization of bile salt deployed nanovesicles as a potential platform for oral delivery of piperine: accentuated antiviral and anti-inflammatory activity in MERS-CoV challenged mice.

The objective of this paper is to confine piperine, a poor oral bioavailable herbal drug into bile salt based nano vesicles for improving its aqueous solubility, hence, its therapeutic activity. Piperine-loaded bilosomes were fabricated adopting thin film hydration technique according to 32.21 full factorial design to investigate the impact of different formulation variables on the characters of bilosomes: entrapment efficiency (EE%), particle size, and % of drug released post 8 h (Q8hr). The selected optimum formula was F2 (enclosing 1% bile salt, brij72 as a surfactant, and ratio of surfactant:cholesterol was 9:1) with desirability value 0.801, exhibiting high EE% (97.2 ± 0.8%) nanosized spherical vesicles (220.2 ± 20.5 nm) and Q8hr (88.2%±5.6). The superiority of the optimized formula (F2) over the drug suspension was revealed via ex vivo permeation study, also pharmacokinetic study denoted to the boosted oral bioavailability of piperine-loaded bilosome compared to piperine suspension. Moreover, antiviral activity and safety margin of F2 was significantly higher than that of the drug suspension. The ability of piperine to interact with the key amino acids in the receptor binding domain 4L3N as indicated by its docking configuration, rationalized its observed activity. Furthermore, F2 significantly reduce oxidant markers, inflammatory cytokines in MERS-CoV-infected mice. Hence, bilosomes can be considered as a carrier of choice for piperine with potential antiviral and anti-inflammatory activities.

Study on the compatibility effect and active constituents of Atractylodis Rhizoma in Ermiao Wan against Acute Gouty Arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ermiao Wan (EMW), composed of Atractylodis Rhizoma (AR) and Phellodendri Chinensis Cortex (PC), is a classical traditional Chinese medicine prescription having been used to treat the disease named "Tong Feng", which is described as "ache in bones and joints" with the same symptom of modern disease named acute gouty arthritis for many years in TCM clinical practice. Besides, both PC and AR were considered to be effective in anti-inflammatory according to modern pharmacological research. AIM OF THE STUDY: Present study was undertaken to probe the compatibility rationality between the two herbs PC and AR in EMW and the active constituents of AR against acute gouty arthritis (AGA). MATERIALS AND METHODS: Rat model of AGA was induced by intra-articular injection of monosodium urate (MSU) crystal suspension, and PC combined with or without different AR extracts were used for AGA treatment. Ankle joint swelling, proinflammatory cytokines in serum and pathological changes of synovium were investigated. Using the developed UHPLC-QQQ-MS method, the plasma concentrations of the primary alkaloids in PC, such as berberine, phellodendrine, magnoflorine, jatrorrhizine, berberrubine, palmatine, and tetrahydropalmatine, in AGA rat were determined, and pharmacokinetics properties were compared following oral administration of PC, PC combined with or without different AR extracts. RESULTS: PC, PC combined with AR volatile oil (VO) extract or PC combined with whole AR extract significantly attenuated the ankle joint swelling of AGA rats. Besides, the combination of PC and VO extract of AR showed superior efficacy than other groups in ameliorating ankle joint swelling, reducing the IL-6 expression in serum and improving tissue lesions of ankle joints. Furthermore, it turned out that the VO extract of AR increased the blood exposure level of PC related alkaloids than non-volatile oil (NVO) extract of AR, by comparing the pharmacokinetic results of each group. CONCLUSIONS: The VO components of AR were the key compatible materials to combine with PC in EMW for AGA treatment. Moreover, the enhanced anti-AGA activity of PC after combining with VO extract of AR may attribute to the influence of VO on the pharmacokinetics of PC. This study may provide useful information for elucidating the compatibility effects of AR in EMW against AGA.

Pharmacokinetics-based chronoefficacy of Fuzi against chronic kidney disease.

OBJECTIVES: Identifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD). METHODS: The Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-ß-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1-/-) mice. KEY FINDINGS: The Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1ß, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy. CONCLUSIONS: The efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.

Pharmacokinetics and tissue distribution study of hupehenenine in rats: A novel isosteroid alkaloid isolated from Bulbus Hupehensis Fritillariae.

Hupehenenine is a novel isosteroid alkaloid that was first isolated from Bulbus Hupehensis Fritillariae. The inhibitory proliferation effect of hupehenenine and its three related alkaloid derivatives, including o-caproyl-hupehenenine, o-(2-furanoyl)-hupehenenine, and Δ5(6) -isopeimine on human lung cancer cell line, human chronic myeloid leukemia cell line, and human thyroid duct cancer cell line in vitro, has been identified. This study first developed a sensitive HPLC-MS/MS method for the simultaneous quantification of hupehenenine and three alkaloid derivatives in rat plasma and tissues. The developed method was validated, and it was linear over the concentration range of 1-800 ng/mL for all analytes with R2 ≥ 0.9939 and 0.9972, respectively, in rat plasma and rat liver homogenate. The lower limit of quantitation was 1 ng/mL for all analytes. The intra-day and inter-day precision and accuracy were satisfactory. This validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of hupehenenine in rats. In pharmacokinetic study, the maximum plasma concentration of rats exists gender difference. Tissue distribution study showed that hupehenenine has good affinity for multiple tissues but is unable to cross the blood-brain barrier. These results may provide a useful reference for further research of hupehenenine and its three related alkaloid derivatives.

Simultaneous determination of five bioactive components of XiaoJin Capsule in normal and mammary gland hyperplasia rat plasma using LC-MS/MS and its application to a pharmacokinetic study.

XiaoJin Capsule (XJC) is a classic Traditional Chinese Medicine formula for clinical treatment of thyroid nodules, mammary gland hyperplasia and breast cancer. For the specification and rational application of XJC in the future, an accurate and specific LC-MS/MS method was developed and validated for quantitative determination of five components in rat plasma after oral administration of XJC. The collected plasma samples were extracted by protein precipitation with methanol-acetonitrile (1:3, v/v) mixture solvent and separated on a C18 column using a gradient elution system. Mass spectrometry was performed on a triple quadrupole mass spectrometer, and samples were detected in positive ionization and multiple reactions monitoring mode. The method was properly validated in terms of linearity, precision, accuracy, recovery, matrix effect and stability. All calibration curves showed good linearity (r2 > 0.9910) over their concentration ranges. The intra- and inter-day precisions (RSD) were within 11.0%, and the LLOQ was 0.1, 0.2, 0.5, 7.5 and 7.5 ng/ml for aconine, songorine, neoline, 3-acetyl-11-keto-ß-boswellic acid and 11-keto-ß-boswellic acid, respectively. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. This established method was successfully applied to a pharmacokinetics study of five compounds after oral administration of XJC to normal and mammary gland hyperplasia model rats.

Pharmacokinetics and Pharmacodynamic Herb-Drug Interaction of Piperine with Atorvastatin in Rats.

Herbals that are widely consumed as therapeutic alternatives to conventional drugs for cardiovascular diseases, may lead to herb-drug interactions (HDIs). Atorvastatin (ATR) is drug of choice for hyperlipidemia and is extensively metabolized through CYP3A4 enzyme. Thus, we postulate that concomitant administration of ATR with piperine (PIP, potent inhibitor of CYP3A4 enzyme)/ridayarishta (RID, cardiotonic herbal formulations containing PIP) may lead to potential HDI. A simple, accurate, sensitive high-performance liquid chromatography-photodiode array detection method using Kromasil-100 C18 column, mobile phase acetonitrile: 30 mM phosphate buffer (55:45 v/v) pH 4.5 with flow rate gradient programming was developed to study the potential HDI in rats. Method was found to be linear (2-100 ng/mL) with Lower Limit of Detection (LLOD) 2 ng/mL. The precision (%CV < 15%), accuracy (-1.0 to -10% R.E) with recoveries above 90% from rat plasma of ATR and IS were obtained. The pharmacokinetic (PK) interactions studies on co-administration of ATR (8.4 mg/kg, p.o.) with PIP (35 mg/kg, p.o.), demonstrated a threefold increase in Cmax of ATR (P < 0.01) with significant increase in AUC0-t/AUC0-∞ compared to ATR alone indicating potential PK-HDI. However co-administration of RID (4.2 mL/kg, p.o.) showed less significant changes (P > 0.05) indicating low HDI. The pharmacodynamic effects/interactions study (TritonX-100 induced hyperlipidemic model in rats) suggested no significant alterations in the lipid profile on co-administration of PIP/RID with ATR, indicating that there may be no significant pharmacodynamic interactions.

Comparative HPLC-MS/MS-based pharmacokinetic studies of multiple diterpenoid alkaloids following the administration of Zhenwu Tang and Radix Aconiti Lateralis Praeparata extracts to rats.

Abstracts Zhenwu Tang (ZWT) is a traditional Chinese medicine that is primarily composed of Radix Aconiti Lateralis Praeparata (FZ) and diterpenoid alkaloids are believed to be the pharmacologically active compounds of ZWT. In this study, the pharmacokinetic profiles of hypaconitine, mesaconitine, aconitine, benzoylmesaconitine, benzoylaconitine, and benzoylhypacoitine were assessed in rats following intragastric ZWT administration. Furthermore, differences in the pharmacokinetic profiles of these six alkaloids were assessed as a function of rat sex and the administration of ZWT or FZ extracts to these animals. Plasma levels of these alkaloids were quantified via HPLC-MS/MS. Significant differences in key pharmacokinetic parameters were observed when comparing rats administered FZ or ZWT. Relative to FZ extract treatment, ZWT administration was associated with Cmax and AUC0-∞ values of benzoylmesaconitine that were about 3.5 and 5.5 times higher. Considerable variations in hypaconitine pharmacokinetic parameters were also revealed between female and male rats. The Cmax and AUC0-∞ of hypaconitine were about 2.5- and 2.7-fold elevated in female rats in comparison with male rats. These results suggested that the other compounds within ZWT can enhance the absorption of benzoylmesaconitine, while hypaconitine exhibits higher bioavailability in female rats, as compared with male rats.

Matrine: A review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches.

ETHNOPHARMACOLOGICAL RELEVANCE: "Dogel ebs" was known as Sophora flavescens Ait., which has been widely utilized in the clinical practice of traditional Chinese Mongolian herbal medicine for thousands of years. Shen Nong's Materia Medica (Shen Nong Ben Cao Jing in Chinese pinyin) recorded that it is bitter in taste and cold in nature with the effect of clearing heat and eliminating dampness, insecticide, diuresis. Due to its extensive application in the fields of ethnopharmacological utilization, the pharmaceutical researches of Sophora flavescens Ait.s keeps deepening. Modern pharmacological studies have exhibited that matrine, which is rich in this traditional herbal medicine, mediates its main biological properties. AIMS OF THE REVIEW: This review aimed at summarizing the latest and comprehensive information of matrine on the pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches to explore the therapeutic potential of this natural ingredient. In addition, outlooks and perspective for possible future researches that related are also discussed. MATERIALS AND METHODS: Related information concerning matrine was gathered from the internet database of Google scholar, Pubmed, ResearchGate, Web of Science and Wiley Online Library with the keywords including "matrine", "pharmacology", "toxicology" and "pharmacokinetics", "clinical application", etc. RESULTS: Based on literatures, matrine has a variety of pharmacological effects, including anti-cancer, anti-inflammatory, anti-microbial, detoxification and so on. Nevertheless, there are still some doubts about it due to the toxicity and questionable bioavailability that does exist. CONCLUSIONS: Future researches directions probably include elucidate the mechanism of its toxicity and accurately tracing the in vivo behavior of its drug delivery system. Without doubt, integration of toxicity and efficiency and structure modification based on it are also pivotal methods to enhance pharmacological activity and bioavailability.

Piperine: A review of its biological effects.

Medicinal plants have been used for years as a source of food, spices, and, in traditional medicine, as a remedy to numerous diseases. Piper nigrum, belonging to the family Piperaceae is one of the most widely used spices all over the world. It has a distinct sharp flavor attributed to the presence of the phytochemical, piperine. Apart from its use as a spice, P. nigrum is frequently used for medicinal, preservation, and perfumery purposes. Black pepper contains 2-7.4% of piperine, varying in content is associated with the pepper plant. Piperine displays numerous pharmacological effects such as antiproliferative, antitumor, antiangiogenesis, antioxidant, antidiabetic, anti-obesity, cardioprotective, antimicrobial, antiaging, and immunomodulatory effects in various in vitro and in vivo experimental trials. Furthermore, piperine has also been documented for its hepatoprotective, anti-allergic, anti-inflammatory, and neuroprotective properties. This review highlights and discusses the medicinal and health-promoting effects of piperine, along with possible mechanisms of its action in health promotion and disease prevention. In addition, the present review summarizes the recent literature related to piperine as a therapeutic agent against several diseases.

Thirteen bisbenzylisoquinoline alkaloids in five Chinese medicinal plants: Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity studies.

RELEVANCE: Bisbenzylisoquinoline (BBIQ) alkaloids are generally present in plants of Berberidaceae, Monimiaceae and Ranunculaceae families in tropical and subtropical regions. Some species of these families are used in traditional Chinese medicine, with the effects of clearing away heat and detoxification, promoting dampness and defecation, and eliminating sores and swelling. This article offers essential data focusing on 13 representative BBIQ compounds, which are mainly extracted from five plants. The respective botany, traditional uses, phytochemistry, pharmacokinetics, and toxicity are summarized comprehensively. In addition, the ADME prediction of the 13 BBIQ alkaloids is compared and analyzed with the data obtained. MATERIALS AND METHODS: We have conducted a systematic review of the botanical characteristics, traditional uses, phytochemistry, pharmacokinetics and toxicity of BBIQ alkaloids based on literatures collected from PubMed, Web of Science and Elsevier during 1999-2020. ACD/Percepta software was utilized to predict the pharmacokinetic parameters of BBIQ alkaloids and their affinity with enzymes and transporters. RESULTS: Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity of 13 alkaloids, namely, tetrandrine, dauricine, curine, trilobine, isotrilobine, cepharanthine, daurisoline, thalicarpine, thalidasine, isotetrandrine, liensinine, neferine and isoliensinine, have been summarized in this paper. It can't be denied that these alkaloids are important material basis of pharmacological effects of family Menispermaceae and others, and for traditional and local uses which has been basically reproduced in the current studies. The 13 BBIQ alkaloids in this paper showed strong affinity and inhibitory effect on P-glycoprotein (P-gp), with poor oral absorption and potent binding ability with plasma protein. BBIQ alkaloids represented by tetrandrine play a key role in regulating P-gp or reversing multidrug resistance (MDR) in a variety of tumors. The irrationality of their usage could pose a risk of poisoning in vivo, including renal and liver toxicity, which are related to the formation of quinone methide during metabolism. CONCLUSION: Although there is no further clinical evaluation of BBIQ alkaloids as MDR reversal agents, their effects on P-gp should not be ignored. Considering their diverse distribution, pharmacokinetic characteristics and toxicity reported during clinical therapy, the quality standards in different plant species and the drug dosage remain unresolved problems.

Polysaccharides of vinegar-baked radix bupleuri promote the hepatic targeting effect of oxymatrine by regulating the protein expression of HNF4α, Mrp2, and OCT1.

ETHNOPHARMACOLOGICAL RELEVANCE: Vinegar-baked Radix Bupleuri (VBRB) is a processed form of Bupleurum chinense DC. As a well-known meridian-guiding drug, it is traditionally used as a component of traditional Chinese medicine formulations indicated for the treatment of liver diseases. However, the liver targeting component in VBRB remains unclear. Therefore, this study aims to explore the efficacy and mechanism of PSS (polysaccharides in Vinegar-baked Radix Bupleuri) in enhancing liver targeting. MATERIALS AND METHODS: Drug distribution of OM alone or combined with PSS was investigated in vivo. Relative uptake efficiency (RUE) and relative targeting efficiency (RTE) were calculated to evaluate liver targeting efficiency. The mRNA and protein expression of organic cation transporter 1 (OCT1), multi-drug resistance protein 2 (Mrp2), and hepatocyte nuclear factor 4α (HNF4α) in the liver were determined by q-PCR and Western blot. Then, AZT, the inhibitor of OCT1 and BI6015, the inhibitor of HNF4α were used to investigate regulatory mechanisms involved in the uptake of OM in the cell. At last, the role of PSS in the anti-hepatitis B virus (HBV) was explored on HepG2.2.15. RESULTS: PSS increased the AUC of OM in the liver and increase the RUE and RTE in the liver which indicated a liver targeting enhancing effect. The mRNA and protein expression of OCT1 was increased while Mrp2 and HNF4α decreased. PSS could increase the uptake of OM in HepG2 by increasing the protein expression of HNF4α and OCT1, while inhibited Mrp2. Moreover, PSS combined with OM could enhance the anti-HBV effect of OM. CONCLUSION: PSS enhanced the liver targeting efficiency and the underlying mechanism related to up-regulating the expression of OCT1 and HNF4α, while down-regulating of Mrp2. These results suggest that PSS may become a potential excipient and provide a new direction for new targeted research.