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Objectives: The novel coronavirus disease-2019 (COVID-19) that emerged in China, is a highly transmittable and pathogenic viral infection caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2); the disease has been declared by the World Health Organization as a Public Health Emergency of International Concern. The unavailability of approved therapeutic agents or vaccines is of great concern. This study performed molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis of some compounds isolated from Neocarya macrophylla (Sabine) Prance ex F. White (Chrysobalanaceae) against three targets of SARS-CoV-2 proteins (3C-like protease, spike protein, and papain-like protease). Materials and Methods: Phytoconstituents isolated from N. macrophylla were screened against key targets of SARS-CoV-2 using Auto Dock Vina, while the ADMET analysis was performed using swiss ADME and pkCSM ADMET descriptors algorithm protocols. Results: The in silico computational studies revealed that the compounds (catechin, catechin-3-rhamnoside, quercetin, and epicatechin) isolated from N. macrophylla can effectively bind with high affinity and lower energy values to the three target proteins of SARS-CoV-2. ADMET analysis was used to predict important pharmacokinetic properties of the compounds, such as aqueous solubility, blood-brain barrier, plasma protein binding, CYP2D6 binding, intestinal absorption, and hepatotoxicity. Conclusion: The findings of this study have shown that N. macrophylla contains potential leads for SARS-CoV-2 inhibition and thus, should be studied further for development as therapeutic agents against COVID-19. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. Methods: A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16 years were proposed by Monte Carlo simulations. Results: A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16 years were proposed based on the final established model. Conclusion: We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications. [ABSTRACT FROM AUTHOR]

Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China. This study aims to investigate the CYP450-mediated reduction responsible for metabolizing OSC and to evaluate the absorption and metabolism of OSC in rat in situ. Four metabolites were identified, with sophocarpine (SC) as the major metabolite. SC formation was rapid in human and rat liver microsomes (HLMs and RLMs, respectively). The reduction rates in the liver are two fold higher than in the intestine, both in humans and rats. In HLMs, inhibitors of CYP2C9, 3A4/5, 2D6, and 2B6 had strong inhibitory effects on SC formation. Meanwhile, inhibitors of CYP3A and CYP2D6 had significant inhibition on SC formation in RLMs. Human recombinant CYP3A4/5, 2B6, 2D6, and 2C9 contributed significantly to SC production. The permeability in rat intestine and the excretion rates of metabolites were highest in the duodenum (p < 0.05), and the absorbed amount of OSC in duodenum and jejunum was concentration-dependent. The metabolism could be significantly decreased by CYP3A inhibitor ketoconazole. In conclusion, the liver was the main organ responsible for OSC metabolism. First-pass metabolism via CYP3A4/5, 2B6, 2D6, and 2C9 may be the main reason for the poor OSC bioavailability. [ABSTRACT FROM AUTHOR]

This study attempted to explore the effects of white pepper and its major component piperine on puerarin administered to rats. Pharmacokinetic parameters of puerarin in rats were determined by oral administration (400mg/kg) or intravenous injection (40mg/kg) of puerarin, pretreated with or without white pepper and piperine given orally. Compared to the control group given oral puerarin only, the combined use of piperine (10 or 20mg/kg) increased the Cmax of puerarin by 1.30-fold or 1.64-fold and the AUC0-∞ by 133% or 157%, respectively. In contrast, coadministration of white pepper (125 or 250mg/kg) decreased oral absorption of puerarin to 83% or 74%, respectively. On the other hand, pretreatment with piperine orally did not alter the intravenous pharmacokinetics of puerarin, while the AUC of puerarin after intravenous administration was increased by pretreatment with white pepper. The results indicate that pretreatment with piperine or pepper exerts different effects on pharmacokinetics of puerarin administrated via intragastric and intravenous routes. Therefore, it is suggested that the combined application of piperine or white pepper with puerarin should be carefully monitored for potential diet-drug interactions. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Traditional Chinese medicine (TCM), used in clinical practice for thousands of years, has been taken as a new way to tackle chronic diseases. In Chinese medicine, many ingredients which are known to have biological effects just pass through the gut, they do not get into the bloodstream. Study on interactions of these active ingredients with the intestinal bacteria is very helpful to unravel how TCM works. Aim of the study: Hyperoside is a major active constituent in many medicinal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory and anti-oxidative effects. It would be metabolized by intestinal bacteria after oral administration which leads to the variation of ethnopharmacological profile of these traditional medicines. Thus, it is necessary to investigate the metabolic routes and metabolites of hyperoside produced by human intestinal bacteria. Materials and methods: Ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/QTOF-MS) technique combined with Metabolynx™ software was used for analysis of the metabolic profile of hyperoside by the isolated human intestinal bacteria from the human feces. Results: Parent compound and 6 metabolites (M1-M7) were detected in the isolated bacterial samples compared with blank samples. Quercetin, 3, 4-dihydroxyphenylacetic acid and 3, 4-dihydroxyphenylbenzoic acid (M2-M4) were only found in the sample of Bacteroides sp. 45. Dehydroxylation of hyperoside and the conjugates: acetylation and hydroxylation of hyperoside (M5–M7) were identified in the majority of isolated intestinal bacterial samples. Conclusions: Only Bacteroides sp. 45 could metabolize hyperoside to form its aglycone quercetin, thereafter, quercetin was further metabolized to 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid. Furthermore, the majority of bacteria could metabolize hyperoside to dehydroxylation of hyperoside and the conjugates: hydroxylation and acetylation of hyperoside. In this study, the metabolic routes and metabolites of hyperoside produced by the different intestinal bacteria were investigated for the first time. Furthermore, the production of metabolites of hyperoside might influence the effects of traditional medicines. Thus, the study on the metabolism of hyperoside by human intestinal bacteria is of great importance to an understanding of the effects of traditional medicines. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Aconitum carmichaelii Debx. (Fuzi in Chinese) has been widely clinically used to treat heart failure and rheumatism. Whereas its serious toxicity, Radix et Rhizoma Glycyrrhizae (Gancao in Chinese) was combined with it as traditional Chinese medicine (TCM) herb-pair for toxicity reduction and pharmacological effect improvement. Though some previous viewpoints about that has been reported, the underlying interaction mechanism of two herbs remain unknown and definitely worthy of investigating. Aim of study: In present study, we focus on Fuzi–Gancao herb-pair precipitation (FGP), considering it related to the compatibility mechanism of Fuzi–Gancao herb-pair. The intestinal absorption and pharmacokinetic characters of 3 diester diterpenoid alkaloids in the precipitation were investigated. Materials and methods: Both everted gut sac model and in situ single-pass intestinal perfusion model were used to investigate rat small intestinal permeability and transport mechanism of aconitine, hypaconitine and mesaconitine. Moreover, by means of determination of the plasma concentration, the pharmacokinetic characters of 3 alkaloid compounds in rats have been developed. Results: In everted gut sac permeability experiment, the permeability of hypaconitine appeared best in ileum. Furthermore, their uptakes were increased in the presence of P-glycoprotein (P-gp) inhibitors. In situ single-pass intestinal perfusion uptake experiment, results revealed that the transport mechanism may fit the active transport mechanism. And 3 alkaloids in FPG could be absorbed well in rats, fitting 2-compartment model with 1st order absorption and lag time. Conclusions: Our results in present study indicated that 3 diester diterpenoid alkaloids in FGP could be dissolved out in gastrointestinal tract firstly and then absorbed in blood after oral administration, which could result in prolonging their mean residence time and adding their absorbed doses, avoiding dose dumping. The current study has significant enlightenments for further investigation on the interaction mechanisms of other acid-base herb-pairs as well as Fuzi–Gancao herb-pair. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (−)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models. Materials and methods: Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose–response curves were plotted and IC50 values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb–drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples. Results: It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites. Conclusions: Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb–drug and herb–herb interactions between B and selected compounds, especially CUR. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Cinnabar (Cin), a naturally occurring mercuric sulfide (HgS), is a mineral widely used in traditional Chinese medicine throughout history. As for the toxicity of cinnabar, one important assumption is that cinnabar may be transformed into highly toxic methylmercury by gastrointestinal flora. There is no evidence in humans to support this assumption. Aim of the study: To investigate the biotransformation of cinnabar (HgS) in the human intestinal bacteria with modern analytical techniques. Materials and methods: A gas chromatograph, equipped with electron capture detection (GC-ECD) and mass spectrometry (GC–MS), were used to detect the formation of methylmercury after incubation of cinnabar with human intestinal bacteria. The content of soluble mercury in the bacteria media was determined by cold vapor-atomic absorption spectrometry (CV-AAS). In addition, X-ray absorption near-edge structure spectroscopy (XANES) was used to confirm the possible transformation of cinnabar in the bacteria media, and under mimetic intestinal condition by measuring the species of sulfur and mercury in the reaction extraction of cinnabar and Na2S mixture. Results: No methylmercury was detected by both GC-ECD and GC–MS, which suggest that cinnabar (HgS) is not methylated in the human intestine. A small amount of soluble mercury was found to be released in the flora medium of HgS or cinnabar by CV-AAS. The XANES analyses revealed that polysulfides exist in the flora medium, and the simulated results showed that the products by incubating cinnabar with Na2S were mercuric polysulfides. Conclusion: These results showed that under gut flora conditions cinnabar would be transformed into mercuric polysulfides rather than methylmercury. Our work provides evidences of nontoxic transformation of cinnabar in the human intestinal bacteria. [Copyright &y& Elsevier]

Abstract: Aim of the study: Aged animals as well as elderly humans commonly exhibit calcium (Ca) shortage because of increased Ca excretion into urine and decreased intestinal Ca absorption, which induce elevation of serum PTH levels to maintain serum Ca levels between a normal physiological range. The most important organ that regulates this Ca homeostasis is the kidney. Hachimijiogan (HJG), a traditional herbal medicine in Japan and China, has been used for treating clinical diseases associated with kidney dysfunctions in elderly humans. However, the mechanisms of its pharmacological actions remain to be understood poorly. The present study was designed to examine whether HJG improves age-related unbalance of Ca metabolism at the systemic level using aged rats. Materials and methods: HJG was administered to 21-month-old aged rats for 3 months, and several parameters associated with Ca metabolism in serum and urine were measured. Results: Although HJG as well as aging itself did not affect serum Ca levels compared to young (11-week-old) rats, HJG improved increase in urinary Ca excretion and elevation of serum parathyroid hormone (PTH) levels in aged rats. However, HJG did not improve marked reduction of intestinal Ca absorption in aged rats. Conclusion: HJG showed regulating action for age-related unbalance of Ca metabolism at the systemic level. This finding would provide useful information for treating age-related several disorders associated with Ca unbalance. [Copyright &y& Elsevier]

The objective of this study was to determine the effect of dietary starch sources on the balance of glucose and amino acids across the portal-drained viscera (PDV) of growing pigs. Four Duroc×Landrance×Yolkshire cross-bred barrows (with an average body wt of 22.5 kg) were housed individually in stainless steel metabolism cages and trained to consume feed provided daily. After a 2-wk adaptation period, pigs were fitted with permanent catheters in the portal vein, mesenteric vein, and carotid artery. After a 13-d recovery period, pigs were assigned randomly into one of 4 treatment groups in a 4×4 Latin square design representing 4 cornstarch- and casein-based isocaloric and isonitrogenous diets containing 52.0% corn, 65.8% brown rice, 65.3% sticky rice, and 51.8% Hi-Maize 1043 (resistant starch). Pigs were fed 3 times daily at 07:30, 15:30 and 23:30 at a feeding level of >963 kJ DE/kg diet. Each diet was fed to the pig after a 6-d adaptation period. On d 7, blood samples were obtained simultaneously from the 3 catheters at 30 min prior to feeding and hourly for 8 h after feeding. Portal blood flow was measured using p-aminohippuric acid. Results showed that portal glucose absorption (expressed per 100 g feed intake) was lower (P < 0.05) for the resistantstarch diet compared with corn, stick rice and brown rice diets at all sampling times. In comparison with the corn diet, net portal glucose absorption was higher (P < 0.05) for the sticky rice and brown rice diets up to 4 h after feeding, but was reduced (P < 0.05) thereafter. Feeding the resistant-starch diet reduced (P < 0.05) the net portal absorption of total amino acids, particularly Pro, Leu, and Ile. The net appearance of total amino acids absorbed from the ileum differed (P < 0.05) among the treatment groups, and was 48.4, 63.8, 61.8, and 59.3%, respectively, for piglets fed the corn, brown rice, sticky rice, and resistant-starch diets. These findings indicate that dietary sources of starch affect intestinal absorption and metabolism of glucose and amino acids in growing pigs. Supported by funds from Chinese Academy of Sciences and China NSF. [ABSTRACT FROM AUTHOR]