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The immediate and delayed metabolic changes in rats treated with valproate (VPA), a drug used for the treatment of epilepsy, were profiled. An established approach using dried blood spots (DBS) as sample matrices for gas chromatography/mass spectrometry-based metabolomics profiling was modified using double solvents in the extraction of analytes. With the modified method, some of the previously undetectable metabolites were recovered and subtle differences in the metabolic changes upon exposure to a single dose of VPA between males and female rats were identified. In male rats, changes in 2-hydroxybutyric acid, pipecolic acid, tetratriacontane and stearic acid were found between the control and treatment groups at various time points from 2.5 h up to 24 h. In contrast, such differences were not observed in female rats, which could be caused by the vast inter-individual variations in metabolite levels within the female group. Based on the measured DBS drug concentrations, clearance and apparent volume of distribution of VPA were estimated and the values were found to be comparable to those estimated previously from full blood drug concentrations. The current study indicated that DBS is a powerful tool to monitor drug levels and metabolic changes in response to drug treatment.

Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug–drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes’ inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.

Propylthiouracil (PTU) is commonly prescribed for the management of hyperthyroidism and thyrotoxicosis. Although the exact mechanism of action is not fully understood, PTU is associated with hepatoxicity in pediatric population. Glucuronidation mediated by uridine 5′-diphospho-glucuronosyltransferases (UGTs), which possess age-dependent expression, has been proposed as an important metabolic pathway of PTU. To further examine the metabolism of PTU, a reliable HPLC-MS/MS method for the simultaneous quantification of PTU and its N-β-D glucuronide (PTU-GLU) was developed and validated. The chromatographic separation was achieved on a ZORBAX Extend-C18 column (2.1 × 50 mm, 1.8 μm) through gradient delivery of a mixture of formic acid, methanol and acetonitrile. The electrospray ionization (ESI) was operated in its negative ion mode while PTU and PTU-GLU were detected by multiple reaction monitoring (MRM). This analytical method displayed excellent linearity, sensitivity, accuracy, precision, recovery and stability while its matrix effect and carry-over were insignificant. Subsequently, the in vitro metabolism of PTU was assessed and UGT1A9 was identified as an important UGT isoform responsible for the glucuronidation of PTU. The information obtained from this study will facilitate future mechanistic investigation on the hepatoxicity of PTU and may optimize its clinical application.

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

Periodontitis is a common chronic inflammatory disease driven by the interaction between a dysbiotic oral microbiome and the dysregulated host immune-inflammatory response. Naturally derived nutraceuticals, such as resveratrol and its analogs, are potential adjunctive therapies in periodontal treatment due to their antimicrobial and anti-inflammatory properties. Furthermore, different analogs of resveratrol and the choice of solvents used may lead to varying effects on therapeutic properties. This review presents the current findings and gaps in our understanding on the potential utility of resveratrol and its analogs in periodontal treatment.

The application of physiologically based pharmacokinetic models to nanoparticles is still very restricted and challenging, owing to the complicated in vivo transport mechanisms involving nanoparticles, including phagocytosis, enhanced permeability and retention effects, cellular recognition, and internalisation, enzymatic degradation, lymphatic transport, and changes in physical properties. In our study, five nanoparticle formulations were synthesised using polycaprolactone as a framework material and methoxy poly (ethylene glycol)-poly(ε-caprolactone) as a long-circulating decorating material, as well as types of environmentally responsive near-infrared aza-boron-dipyrromethene dyes. According to quantification data and direct visualisation involving specific organs, a phagocytosis physiologically based pharmacokinetic model was developed to describe the dynamics of nanoparticles within and between organs in mice, considering cellular mechanisms involving phagocytosis and enhanced permeability and retention effects. Our results offer a better understanding of the in vivo fate of polymeric nanoparticles.

Artemether, an artemisinin derivative, is used in the management of life-threatening severe malaria. This study aimed to develop an intravenous dosage form of artemether using nanotechnology. Artemether-loaded zein nanoparticles were prepared by modified antisolvent precipitation using sodium caseinate as a stabilizer. Subsequently, the physicochemical properties of the nanoparticles were characterized, the in vitro hemolytic property was examined with red blood cells, while the pharmacokinetic profile was evaluated in Sprague&ndash, Dawley rats after intravenous administration. The artemether-loaded zein nanoparticles were found to display good encapsulation efficiency, excellent physical stability and offer an in vitro extended-release property. Interestingly, encapsulation of artemether into zein nanoparticles substantially suppressed hemolysis, a common clinical phenomenon occurring after artemisinin-based antimalarial therapy. Upon intravenous administration, artemether-loaded zein nanoparticles extended the mean residence time of artemether by ~80% in comparison to the free artemether formulation (82.9 &plusmn, 15.2 versus 45.6 &plusmn, 16.4 min, p &lt, 0.01), suggesting that the nanoparticles may prolong the therapeutic duration and reduce the dosing frequency in a clinical setting. In conclusion, intravenous delivery of artemether by artemether-loaded zein nanoparticles appears to be a promising therapeutic option for severe malaria.

The risk of drug-induced liver injury (DILI) poses a major challenge for development of natural products derived from traditional Chinese medicines (NP-TCMs). It is urgent to find a new method for the safety assessment of the NP-TCMs. Recent study has reported an in vitro/in silico method to estimate the acceptable daily intake of hepatotoxic compounds using support vector machine (SVM) classifier and physiologically based pharmacokinetic (PBPK) modeling. However, this method is not suitable for estimating the dosing schedule of compounds which are administered in multiple daily doses. Thus, in this study, the method mentioned above was in particular optimized, and used to estimate the hepatotoxic plasma concentrations of 17 NP-TCMs. Additionally, the oral dosing schedules of the triptolide, emodin, matrine and oxymatrine were also predicted by the SVM classifier and PBPK modeling. The optimization included that: (1) in vitro cytotoxicity data of 28 training set compounds was optimized using benchmark concentrations (BMC) modeling; (2) AUC of the training set compound was used as the in vivo metric instead of Cmax to better reflect the total daily exposure of compounds which are administered in multiple daily doses; (3) using the mean AUC in plasma as in vivo metric and BMC value as in vitro metric could achieve the better toxicity separation index (0.962 vs. 0.938); (4) The TSI for Cmax and BMC values was 0.985 calculated in this study, and the results indicated that BMC modeling improved the separation performance. This optimized in vitro-in vivo extrapolation (IVIVE) workflow could extrapolate in vitro BMC to blood concentrations and the oral dosing schedule which are corresponding to certain risk of hepatotoxicity. The estimated safe dosing schedule of oxymatrine by this optimized method was close to the clinical recommended dosing regimen. The results indicate that the optimized method could be used to predict the dosing schedule of compounds administered in multiple daily doses, and our optimized workflow could be helpful for the safety assessment as well as the research and development on NP-TCMs.

Resveratrol (RES) is a natural polyphenol with potential as an adjunctive therapeutic modality for periodontitis. However, its inferior pharmacokinetics and toxicity concerns about its commonly used solvent dimethyl sulfoxide (DMSO) hinder translation to clinical applicability. Our study aimed to investigate the comparative antimicrobial properties of RES and its analogues (pterostilbene [PTS], oxyresveratrol [OXY] and piceatannol [PIC]), utilizing 2-hydroxypropyl-β-cyclodextrin (HPβCD) as a solubiliser, which has a well-documented safety profile and FDA approval. These properties were investigated against Fusobacterium nucleatum, a key periodontal pathogen. PTS demonstrated the most potent antibacterial effects in HPβCD, with MIC > 60-fold lower than that of RES, OXY and PIC. In addition, PTS inhibited F. nucleatum biofilm formation. PTS exerted antimicrobial effects by eliciting leakage of cellular contents, leading to loss of bacterial cell viability. PTS also conferred immunomodulatory effects on F. nucleatum-challenged macrophages via upregulation of antioxidant pathways and inhibition of NF-κB activation. Given the superior antimicrobial potency of PTS against F. nucleatum compared to RES and other analogues, and coupled with its immunomodulatory properties, PTS complexed with HPβCD holds promise as a candidate nutraceutical for the adjunctive treatment of periodontitis.

Severe malaria is potentially life-threatening and requires the parenteral administration of the artemisinin-based formulation for short duration of action. Intravenous artemether formulation has shown potentially better therapeutic efficacy but its poor aqueous dissolution constitutes a challenge. This work produced human serum albumin (HSA)-bound artemether nanoparticles by emulsification and desolvation approach using nanoparticle albumin bound (nab) technology for intravenous (IV) administration. The prepared nanoparticles had a size below 50 nm. It was observed that higher HSA concentration; lower drug concentration and longer ultrasonication time (up to 60 s) favoured the production of smaller particles. Comparatively, the emulsification method allowed for higher drug entrapment per the same concentration of HSA and required less organic solvent, less water and less energy and is therefore the preferred method. HSA-bound artemether nanoparticles displayed significantly enhanced dissolution properties over raw artemether. In-vitro haemolysis studies demonstrated a significant decrease in haemolysis caused by artemether from 101% to 7% in the emulsification product and to 4% by the desolvation product.

Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE) is a naturally occurring polymethoxyflavone with a wide range of health-promoting activities. In this study, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of ATE in rat plasma. Protein precipitation was applied as plasma clean-up procedure; the electrospray ionization was operated in its positive ion mode while ATE and formononetin (internal standard) were measured by multiple reactions monitoring (ATE: m/z 313.1→298.1; formononetin: 269.2→213.3). This LC-MS/MS method displayed good selectivity, sensitivity (lower limit of quantification=2.5ng/ml), accuracy (both intra- and inter-day analytical recovery within 100±10%) and precision (both intra- and inter-day RSD

Background and Purpose Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo. Experimental Approach Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague–Dawley rats. Key Results Isorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC50 values at least twofold lower than those of resveratrol. These were associated with reduced activation of NF-κB and AP-1 and, notably, the PI3K/Akt/FoxO3A pathway, that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma levels after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol. Conclusions and Implications Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.

Scope To evaluate the health-promoting potentials of piceatannol (PIC), a dietary resveratrol derivative, its biotransformation is examined. Methods and results The biotransformation is tested in human/rat hepatic microsomes and cytosols; its pharmacokinetic profiles are assessed in rats. Although limited phase I metabolism exists in microsomes, PIC is rapidly converted to two pharmacologically active metabolites, namely rhapontigenin (RHA) and isorhapontigenin (ISO) in cytosols. Such biotransformation is completely blocked by entacapone, a well-known catechol-O-methyltransferase (COMT) inhibitor, demonstrating that the O-methylation is mediated by COMT. Moreover, PIC is identified as a substrate inhibitor of COMT, suggesting its potential benefits in Alzheimer's disease. Due to extensive phase II metabolism including glucuronidation, sulfation, and O-methylation, PIC displays rapid clearance and at least 4.02% ± 0.61% and 17.70% ± 0.91% of PIC is converted to RHA and ISO, respectively, in rats after intravenous administration. Similarly, PIC serves as an effective precursor of ISO upon oral administration. Conclusion Since PIC and its metabolites possess pleiotropic health-promoting activities, it has emerged as a promising nutraceutical candidate for further development. This study also reinforces the importance of in vivo testing in nutritional researches as the active metabolite(s) may be absent from the in vitro system.

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug-induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug-metabolizing enzymes and drug transporters have been associated with drug-induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug-metabolizing enzymes and drug transporters to the MMI-DILI. A total of 44 GD patients with MMI-DILI and 118 GD patients without MMI-DILI development were included in the study. Thirty-three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI-DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI-DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11-4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29-0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI-DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI-induced hepatotoxicity.

Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5, SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

To evaluate the potential of oxyresveratrol (OXY), a dietary polyphenol with various health-promoting activities as a nutraceutical/functional food ingredient, its absolute oral bioavailability ( F ) was examined in Sprague-Dawley rats. Upon single intravenous administration (15 µmol/kg), rapid clearance ( Cl ) and short mean transit time ( MTT ) was observed. Dose-escalation to 90 µmol/kg did not alter its Cl and MTT significantly. After single oral administration (100 µmol/kg), although its F was only ~10%, OXY was absorbed rapidly and displayed long residence in systemic circulation. Dose-escalation to 400 µmol/kg brought ~60% and 100% increase in F and dose-normalized maximal plasma concentration ( C max ), respectively. One-week daily dosing (100 µmol/kg) did not cause substantial change in F and C max . Although OXY possessed slower Cl , its oral plasma exposure was comparable to RES. As OXY was orally bioavailable, further development of OXY as a nutraceutical/functional food ingredient is warranted.

Pinostilbene (3-methoxyresveratrol or trans-3,4'-dihydroxy-5-methoxystilbene) is a naturally occurring monomethylether analogue of resveratrol (trans-3,5,4'-trihydroxystilbene) that exhibits various pharmacological activities. To further examine its medicinal potential, a sensitive LC-MS/MS method was developed and validated for the determination of pinostilbene in rat plasma. Heavy Isotope labelled resveratrol was used as an internal standard. The ESI was operated in its negative ion mode while pinostilbene and resveratrol were measured by multiple reaction monitoring (MRM) using precursor-to-product ion transitions of m/z 241→181 and m/z 233→191, respectively. This LC-MS/MS method had excellent selectivity, sensitivity (LLOQ=1ng/ml), accuracy (both intra- and interday analytical recovery within 100±15%) and precision (both intra- and interday RSD < 15%). The matrix effect was insignificant. The pharmacokinetics of pinostilbene was subsequently profiled in Sprague-Dawley rats. Upon intravenous administration (5 or 10mg/kg), pinostilbene displayed rapid clearance (Cl=129±42 or 107±31ml/min/kg) and extremely short mean transit time (MTT=6.24±0.41 or 8.52±1.38min). After oral dosing (50mg/kg), the bioavailability of pinostilbene was limited but highly erratic (F=1.87±2.67%). Pharmacokinetic comparison among pinostilbene, resveratrol and some resveratrol analogues suggested that stilbenes with meta-hydroxyl group(s) may be associated with metabolic instability and subsequently suffer from rapid clearance and low oral bioavailability. The information obtained from this study will facilitate further exploration on pinostilbene as well as other resveratrol analogues.

Plasma protein binding (PPB) is a key player of drug ADME (absorption, distribution, metabolism, elimination) behaviors, enabling PPB to have significant impact on drug efficacy and toxicity. As drug discovery enters the era of rational drug design, it is desirable to use in silico model to predict PPB so as to achieve rapid initial screening for potential candidate compounds prior to further time-consuming and costly in vitro and in vivo experimental assay. In this study, a global quantitative structure-activity relationship (QSAR) model of PPB was built on the basis of a large training set comprising more than 5000 compounds to represent large structural diversity. The uneven distribution of PPB was often rectified by two mathematical transformations of PPB but this led to a decrease in prediction accuracy at the lower binding level. To resolve this problem, we proposed a novel strategy to build models for different binding levels. The best model yielded much lower mean absolute error (MAE) of 0.076 on the test set than published models and the MAE was further reduced to 0.041 ​at the high level of binding (0.8–1). The models also performed excellent in the validation set containing some compounds from traditional Chinese medicine. In addition, the applicability domain was determined to identify new compounds which are appropriate for prediction using our built models. In conclusion, this study developed a novel strategy to construct robust QSAR model for PPB prediction which could be used by chemists to predict the PPB of candidate compounds efficiently and make structural modification in the early stage of drug development.

Apigenin trimethyl ether (5,7,4′-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. Upon single intravenous administration (2 mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8 mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45 mg/kg, much longer mean residence time (MRT0→last), higher dose-normalized maximal plasma concentration (Cmax/Dose) and exposure (AUC/Dose) were observed at 15 and/or 45 mg/kg. One-week daily oral administration of ATE at 15 mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2 mg/kg) and oral administration (15 mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger.

The metabolism of a promising antineoplastic agent, trans-2,6-difluoro-4′-(N,N-dimethylamino)stilbene (DFS), was studied in mouse, rat, and human liver microsomes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the multiple reaction monitoring-information-dependent acquisition-enhanced product ion scan (MRM-IDA-EPI) method. Ten putative metabolites were identified and the structures of four metabolites were confirmed using authentic standards. Since trans-2,6-difluoro-4′-(N-methylamino)stilbene (DMDFS, M1) was present in all species as metabolite and displayed in vitro growth inhibition superior to DFS, its pharmacokinetic profiles were examined in Sprague–Dawley rats using DFS as a comparator. A reliable LC-MS/MS multiple reaction monitoring (MRM) method was subsequently developed and validated for the simultaneous quantification of both DFS and DMDFS in rat plasma for this purpose. Upon intravenous administration (4 mg/kg), DFS had a moderate clearance (Cl = 62.7 ± 23.2 mL/min/kg), terminal elimination half-life (t 1/2 λZ = 299 ± 73 min), and mean transit time (MTT = 123 ± 14 min) with demethylation metabolism accounting for about 10 % of its total clearance. DMDFS possessed an intravenous pharmacokinetic profile similar to DFS. During oral dosing (10 mg/kg) where both DFS and DMDFS were absorbed rapidly, the oral bioavailability of DFS was approximately 2-fold greater than that of DMDFS (DFS: F = 42.1 ± 12.8 %; DMDFS: F = 18.7 ± 3.9 %). Interestingly, the DMDFS exposure after oral dosing of DFS (10 mg/kg) was comparable to that after oral administration of DMDFS (10 mg/kg) alone. As DFS displayed potent anticancer activities and excellent pharmacokinetic profiles, it appears to be a favorable candidate for further pharmaceutical development.

Desoxyrhapontigenin (DRG, 4-methoxyresveratrol or trans-3,5-dihydroxy-4'-methoxystilbene) is a naturally occurring resveratrol (RES) derivative with a variety of biological activities. To facilitate its further medicinal exploration, a reliable LC-MS/MS method was developed and validated for the quantification of DRG in rat plasma using heavy isotope labelled RES as an internal standard. The ESI was operated in its negative ion mode while DRG and RES were determined by multiple reaction monitoring (MRM) using precursor-to-product ion transitions of m/z 241.1 → 180.8 and m/z 233.0 → 191.0, respectively. This LC-MS/MS method displayed excellent selectivity, sensitivity (LLOQ = 2.5 ng/ml), accuracy (both intra- and interday mean analytical recovery within 100 ± 15%) and precision (both intra- and interday CV 15%). The mean matrix factors were all within 1.000 ± 0.150 with CV 15%. The pharmacokinetic profiles of DRG were subsequently examined in Sprague-Dawley rats. Upon intravenous administration (4 or 10 mg/kg), DRG displayed very rapid clearance (Cl = 338 ± 66 or 275 ± 30 ml/min/kg) and short mean residence time (MRT = 12.9 ± 4.7 or 10.4 ± 0.5 min). After oral administration of DRG fully solubilized by 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), the plasma profiles of DRG were highly erratic with a low absolute bioavailability (F 9.83 ± 5.31%). When DRG was given at a higher dose (50 mg/kg) in suspension form, the F was increased to 24.1 ± 5.6%. The pharmacokinetic comparison among DRG, RES and some of its hydroxyl analogues stilbenes was performed. The information obtained from this study will facilitate further exploration on DRG as well as other RES derivatives.

Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.

Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin’s and its lactone’s metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.

Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo.Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats.Isorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with ICIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.

trans-4,4′-Dihydroxystilbene (DHS) is a naturally occurring resveratrol analog that displayed promising anti-cancer activities in pre-clinical studies. To further probe its therapeutic potential, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the measurement of DHS in rat plasma using electrospray ionization and multiple reaction monitoring in its negative ion mode. This analytical method demonstrated excellent linearity (R 2 > 0.99), selectivity, sensitivity (with a lower limit of quantification of 2.0 ng/mL), accuracy (both intra- and inter-day analytical recovery within 100 ± 15 %) and precision (both intra- and inter-day relative standard deviation within 10 %). The pharmacokinetic profiles of DHS were subsequently assessed in Sprague–Dawley rats. Following intravenous injection (4 mg/kg), DHS had a moderate apparent volume of distribution of the central compartment (V c = 887 ± 297 mL/kg), clearance (Cl = 44.7 ± 5.1 mL/min/kg) and a relatively short mean transit time (MTT = 24.1 ± 8.8 min). When it was given as an oral suspension (10 mg/kg), DHS was absorbed slowly (t max 180 or 300 min) with very limited plasma exposure and absolute oral bioavailability (F = 2.22 ± 0.72 %). On the other hand, when DHS was fully solubilized by hydroxypropyl-β-cyclodextrin, it was absorbed rapidly (t max 30 or 45 min) with more than 15-fold increase in maximal plasma concentration (C max), plasma exposure (AUC 0→last) and bioavailability (F = 36.3 ± 4.8 %). Statistical comparison provided clear evidence that DHS was better than resveratrol from the perspective of pharmacokinetics. In conclusion, further explorations of DHS as an anti-cancer agent are warranted.

The natural mineral orpiment (As2S3) has long been used in traditional medicines for various diseases, although it is poorly soluble and has resulting low bioavailability. In this study, orpiment quantum dots (QDs) belonging to rare V–VI binary QDs were first synthesised through top-down and bottom-up routes, in which a mixture of ethanolamine and triethanolamine was used as a coordinating solvent. The as-synthesised orpiment QDs have a narrow size distribution, superior solubility, strong blue photoluminescence emission, and good stability. Preliminary in vitro cytotoxicity studies show that orpiment QDs are less cytotoxic for human normal dermal fibroblast cells but more potent against murine melanoma B16 cells through induction of apoptosis. Moreover, self-assemblies of orpiment QDs were fabricated through destroying the protective surface ligand layer surrounding the inner orpiment cores by addition of an acid. The underlying driving force is probably competitive reactions between the surface amine ligand and the introduced acid, leading to the exposure of the bare inner orpiment cores with high surface energy.

Quantum dots (QDs) possess unique properties that are expected for various applications. Herein, realgar (As4S4) QDs were synthesized via a wet chemical method in a coordinating solvent (e.g., ethanolamine (EA)) with assistance of an acid (e.g., citric acid (CA)). The as-prepared realgar QDs using EA and CA have a narrow size distribution with a mean value of 5.48[Formula: see text]nm and a relative standard deviation of [Formula: see text]20%, and exhibit bright photoluminescence (PL) in a short wavelength window ([Formula: see text] 480[Formula: see text]nm) with high quantum yield up to 70%. Moreover, realgar QDs can retain their high PL after one-year storage, indicating their excellent stability. Bulk realgar is a commonly used traditional medicine, however, its water-insolubility limits its broad applications. Realgar QDs could be an alternative for the bulk realgar owing to their excellent water-solubility and efficient PL. In preliminary in vivo toxic and pharmaceutical experiments, the synthesized realgar QDs at a single oral dose of 10.0[Formula: see text]mg realgar/kg body weight for 21 days showed tolerability in healthy mice and effective against tumor-bearing nude mice, respectively. In this study, assembly of realgar QDs into specific hollow nanospheres was first constructed by introducing an acid into their original colloidal solution. Simple dissolution of such assemblies in EA can partially return them into the fluorescent QDs. Such property is desired for a variety of media-responsive luminescence materials. In addition, a flexible inorganic/organic hybrid composite film was fabricated for the first time by incorporation of realgar QDs into polyvinyl alcohol matrix. The resulting film presents excellent PL, good transparency, intense mechanical strength and facile processibility, which meet the requirements for device integration.