Intermolecular correlations of liquid and glassy CS2 studied by synchrotron radiation x-ray diffraction.

How is the orientation of molecular liquids ordered on cooling? What are the basic structures of molecular glasses, e.g., close to the crystalline structure or some special structures such as icosahedral cluster? These are long-standing questions in liquid and glass physics. We have constructed a novel cryostat to prepare simple molecular glasses by vapor deposition and performed in situ synchrotron radiation x-ray diffraction experiments. The glassy state of a simple molecule CS2, which cannot be vitrified by normal liquid quenching, was successfully prepared with this instrument, and its diffraction data were collected in a wide Q-range of 0.16-25.7 Å-1 with a high-energy diffractometer at BL04B2, SPring-8. The diffraction data of liquid CS2 were also recorded in a wide temperature range of 160-300 K. These diffraction data were analyzed with molecular dynamics simulations and reverse Monte Carlo modelings to investigate orientational correlation. From the obtained 3D structure models, the orientational correlation between neighboring CS2 molecules was investigated quantitatively as a function of temperature. At room temperature, the parallel and T-shaped arrangements are preferred for the nearest neighbor correlation. On cooling, these arrangements are developed gradually, and its rate became prominent below the melting temperature (162 K). In the glassy state, the slipped-parallel arrangement is dominant as well as the T-shaped arrangement. Both arrangements appear in the CS2 crystal, indicating that the structure of glassy CS2 is close to that of crystalline CS2.

Structural analysis and potential extraction from diffraction data of disordered systems by least-biased feature matching.

Determining the structure and underlying potential from the experiment data is an important task in the study of disordered systems such as liquids and glasses. In this article, a new approach to tackle this problem is proposed. This method can iteratively refine any interaction potential u with the form of a fixed potential ψ added by a dot product between adjustable parameter θ and some functions of atomic coordinates called features f (i.e., potential u = ψ + θ · f). The updating rule for parameters is very simple as it only uses the difference of the ensemble mean of f between the simulation box and experiment. The solution found by this method minimizes the Kullback-Leibler divergence of the atomic distribution under the parameterized potential u and the prior potential ψ, subject to the condition that the ensemble mean of f of the simulation box is equal to its experimental value, ensuring that the potential given will be the least biased one from the prior potential but still consistent with the experiment. It is also shown that this method approximately minimizes the squared difference between the parameterized potential and the unknown true potential. Furthermore, the flexibility of the potential functional form allows the potential to be automatically fitted to some convenient forms or to encode additional known properties of the system under study. The method is tested on Lennard-Jones liquid as well as SiO2 liquid and glass for potential extraction or structure refinement using simulated data and real experiment data. Good results are obtained for both systems.

An adiabatic method to train binarized artificial neural networks.

An artificial neural network consists of neurons and synapses. Neuron gives output based on its input according to non-linear activation functions such as the Sigmoid, Hyperbolic Tangent (Tanh), or Rectified Linear Unit (ReLU) functions, etc.. Synapses connect the neuron outputs to their inputs with tunable real-valued weights. The most resource-demanding operations in realizing such neural networks are the multiplication and accumulate (MAC) operations that compute the dot product between real-valued outputs from neurons and the synapses weights. The efficiency of neural networks can be drastically enhanced if the neuron outputs and/or the weights can be trained to take binary values [Formula: see text] only, for which the MAC can be replaced by the simple XNOR operations. In this paper, we demonstrate an adiabatic training method that can binarize the fully-connected neural networks and the convolutional neural networks without modifying the network structure and size. This adiabatic training method only requires very minimal changes in training algorithms, and is tested in the following four tasks: the recognition of hand-writing numbers using a usual fully-connected network, the cat-dog recognition and the audio recognition using convolutional neural networks, the image recognition with 10 classes (CIFAR-10) using ResNet-20 and VGG-Small networks. In all tasks, the performance of the binary neural networks trained by the adiabatic method are almost identical to the networks trained using the conventional ReLU or Sigmoid activations with real-valued activations and weights. This adiabatic method can be easily applied to binarize different types of networks, and will increase the computational efficiency considerably and greatly simplify the deployment of neural networks.

Effect of Phosphorus Modification on the Acidity, Nanostructure of the Active Phase, and Catalytic Performance of Residue Hydrodenitrogenation Catalysts.

A series of NiMoP(x)-Al catalysts with different phosphorus contents were prepared by the incipient wetness co-impregnation method. The effects of phosphorus modification on the acidity, active phase nanostructure, and catalytic properties of the residue hydrodenitrogenation catalysts were investigated to find the role of phosphorus in the catalytic mechanism. The results of temperature-programmed desorption of NH3 and pyridine IR spectroscopy of the catalysts indicate that phosphorus modification can increase the total acid and Brønsted acid. Transmission electron microscopy analysis shows that phosphorus modification increases the stacking number N A, reduces the slab length L A of the active MoS2 phase, and increases the Mo dispersion f Mo, leading to the promotion of the sulfidation degree of the active Mo phase and thus increasing the denitrification rate. The catalyst with a 3.4 wt % P2O5 loading shows the highest Brønsted/Lewis acid ratio, the largest amount of three-layer active phases, the smallest L A, the highest f Mo, the optimal sulfurization degree, and the highest denitrification rate, 63.6%, indicating the correlation between the nanostructure of the active phase and its catalytic property because of the addition of phosphorus.

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data.

BACKGROUND AND OBJECTIVE: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. METHODS: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. RESULTS: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. CONCLUSION: The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

Mass Spectrometry Imaging: Applications in Drug Distribution Studies.

In the past decade, mass spectrometry imaging (MSI) has received an increasing amount of attention due to its ability in displaying the spatial distribution of a wide range of molecules, including peptides, proteins, lipids, endogenous and exogenous metabolites, and xenobiotics in biological tissues. Information regarding drug localization within tissues provides a better understanding of pharmacokinetic behaviors and pharmacological and toxicological effects. This review presents an introduction to MSI, along with an in-depth analysis of its general process. In addition, we highlighted several examples of various intensive applications of imaging drugs and metabolites in tissues by mass spectrometry. Furthermore, we present the prospect of quantitative MSI of small molecular chemicals, which may be particularly attractive to researchers in the pharmaceutical industry today. It is expected that with technological advancement, MSI will become an increasingly powerful tool in drug disposition studies and other fields of biomedical research.

Identification of known chemicals and their metabolites from Alpinia oxyphylla fruit extract in rat plasma using liquid chromatography/tandem mass spectrometry (LC-MS/MS) with selected reaction monitoring.

Alpinia oxyphylla (Yizhi) capsularfruits are commonly used in traditional medicine. Pharmacological studies have demonstrated that A. oxyphylla capsularfruits have some beneficial roles. Besides volatile oil, sesquiterpenes, diarylheptanoids and flavonoids are main bioactive constituents occurring in the Yizhi capsularfruits. The representative constituents include tectochrysin, izalpinin, chrysin, apigenin-4',7-dimethylether, kaempferide, yakuchinone A, yakuchinone B, oxyphyllacinol and nootkatone. Their content levels in the fruit and its pharmaceutical preparations have been reported by our group. The nine phytochemicals are also the major components present in the Yizhi alcoholic extracts, which have anti-diarrheal activities. However, the fates of these constituents in the body after oral or intravenous administration remain largely unknown. In the present study, we focus on these phytochemicals albeit other concomitant compounds. The chemicals and their metabolites in rat plasma were identified using liquid chromatography/tandem mass spectrometry with selected reaction monitoring mode after orally administered Yizhi extract to rats. Rat plasma samples were treated by methanol precipitation, acidic or enzymatic hydrolysis. This target analysis study revealed that: (1) low or trace plasma levels of parent chemicals were measured after p.o. administration of Yizhi extract, Suoquan capsules and pills to rats; (2) flavonoids and diarylheptanoids formed mainly monoglucuronide metabolites; however, diglucuronide metabolites for chrysin, izalpinin and kaempferide were also detected; (3) metabolic reduction of Yizhi diarylheptanoids occurred in rats. Yakuchinone B was reduced to yakuchinone A and then to oxyphyllacinol in a stepwise manner and subsequently glucuronidated by UDP-glucuronosyl transferase. Further research is needed to characterize the UDP-glucuronosyl transferase and reductase involved in the biotransformation of Yizhi chemicals.

Different accumulation profiles of multiple components between pericarp and seed of Alpinia oxyphylla capsular fruit as determined by UFLC-MS/MS.

Plant secondary metabolites are known to not only play a key role in the adaptation of plants to their environment, but also represent an important source of active pharmaceuticals. Alpinia oxyphylla capsular fruits, made up of seeds and pericarps, are commonly used in traditional East Asian medicines. In clinical utilization of these capsular fruits, inconsistent processing approaches (i.e., hulling pericarps or not) are employed, with the potential of leading to differential pharmacological effects. Therefore, an important question arises whether the content levels of pharmacologically active chemicals between the seeds and pericarps of A. oxyphylla are comparable. Nine secondary metabolites present in A. oxyphylla capsular fruits, including flavonoids (e.g., tectochrysin, izalpinin, chrysin, apigenin-4',7-dimethylether and kaempferide), diarylheptanoids (e.g., yakuchinone A and B and oxyphyllacinol) and sesquiterpenes (e.g., nootkatone), were regarded as representative constituents with putative pharmacological activities. This work aimed to investigate the abundance of the nine constituents in the seeds and pericarps of A. oxyphylla. Thirteen batches of A. oxyphylla capsular fruits were gathered from different production regions. Accordingly, an ultra-fast high performance liquid chromatography/quadrupole tandem mass spectrometry (UFLC-MS/MS) method was developed and validated. We found that: (1) the nine secondary metabolites were differentially concentrated in seeds and fruit capsules; (2) nootkatone is predominantly distributed in the seeds; in contrast, the flavonoids and diarylheptanoids are mainly deposited in the capsules; and (3) the content levels of the nine secondary metabolites occurring in the capsules varied greatly among different production regions, although the nootkatone levels in the seeds were comparable among production regions. These results are helpful to evaluating and elucidating pharmacological activities of A. oxyphylla capsular fruits. Additionally, it may be of interest to elucidate the mechanisms involved in the distinct accumulation profiles of these secondary metabolites between seeds and pericarps.

A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans.

BACKGROUND AND PURPOSE: Alvespimycin, a new generation of heat shock protein 90 (Hsp90) inhibitor in clinical trial, is a promising therapeutic agent for cancer. Pharmacokinetic models of alvespimycin would help in the understanding of drug disposition, predicting drug exposure and interpreting dose-response relationship. In the present study we aimed to develop a physiologically based pharmacokinetic (PBPK) model of alvespimycin in mice and evaluate the utility of the model for predicting alvespimycin disposition in other species. EXPERIMENTAL APPROACH: A literature search was performed to collect pharmacokinetic data for alvespimycin. A PBPK model was initially constructed to demonstrate the disposition of alvespimycin in mice, and then extrapolated to rats and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters. KEY RESULTS: A PBPK model, employing a permeability-limited model structure and saturable tissue binding, was built in mice. It successfully characterized the time course of the disposition of alvespimycin in mice. After extrapolation to rats, the model simulated the alvespimycin concentration-time profiles in rat tissues with acceptable accuracies. Likewise, a reasonable match was found between the observed and simulated human plasma pharmacokinetics of alvespimycin. CONCLUSIONS AND IMPLICATIONS: The PBPK model described here is beneficial to the understanding and prediction of the effects of alvespimycin in different species. It also provides a good basis for further development, which necessitates additional studies, especially those needed to clarify the in-depth mechanism of alvespimycin elimination. A refined PBPK model would benefit the understanding of dose-response relationships and optimization of dosing regimens.

Are circulating metabolites important in pharmacokinetic drug-drug interactions? A retroanalysis of clinical data.

Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently, regulatory bodies have proposed that metabolites at ≥25% of the parent drug's area under the time-concentration curve (AUC) and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs and their metabolites meeting the official guidance's criteria for DDI studies, and to assess whether the eligible drugs caused significant clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8 drugs (~9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drugmetabolite pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic. However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic.

Quantitative evaluation of drug-drug interaction potentials by in vivo information- guided prediction approach.

Drug-drug interaction (DDI) is one important topic in drug discovery, drug development and clinical practice. Recently, a novel approach, in vivo information-guided prediction (IVIP), was introduced for predicting the magnitude of pharmacokinetic DDIs which are caused by changes in cytochrome P450 (CYP) activity. This approach utilizes two parameters, i.e. CR (the apparent contribution of the target metabolizing enzyme to the clearance of the substrate drug) and IX (the apparent effect of a perpetrator on the target CYP) to describe the magnitude of DDI between a perpetrator and a victim drug. The essential concept of this method assumes that at a given dose level, the IX for a given perpetrator remains constant whatever the victim drug is. Usually, this IVIP method is only based on information from clinical studies and does not need in vitro information. In this review, basic concept, application and extension, as well as pros and cons of the IVIP method were presented. How to apply this approach was also discussed. Thus far, this method displayed good performance in predicting DDIs associated with CYPs, and can be used to forecast the magnitude of a large number of possible DDIs, of which only a small portion have been investigated in clinical studies. The key concept of this static approach could even be implemented in dynamic modeling to assess risks of DDIs involving drug transporters.

Physiologically based pharmacokinetic modelling and in vivo [I]/K(i) accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate.

BACKGROUND AND PURPOSE: In vitro inhibitory potency (Ki )-based predictions of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) are hampered by the substantial variability in inhibitory potency. In this study, in vivo-based [I]/Ki values were used to predict the DDI risks of a P-gp substrate dabigatran etexilate (DABE) using physiologically based pharmacokinetic (PBPK) modelling. EXPERIMENTAL APPROACH: A baseline PBPK model was established with digoxin, a known P-gp substrate. The Km (P-gp transport) of digoxin in the baseline PBPK model was adjusted to Km (i) to fit the change of digoxin pharmacokinetics in the presence of a P-gp inhibitor. Then 'in vivo' [I]/Ki of this P-gp inhibitor was calculated using Km (i) /Km . Baseline PBPK model was developed for DABE, and the 'in vivo' [I]/Ki was incorporated into this model to simulate the static effect of P-gp inhibitor on DABE pharmacokinetics. This approach was verified by comparing the observed and the simulated DABE pharmacokinetics in the presence of five different P-gp inhibitors. KEY RESULTS: This approach accurately predicted the effects of five P-gp inhibitors on DABE pharmacokinetics (98-133% and 89-104% for the ratios of AUC and Cmax respectively). The effects of 16 other P-gp inhibitors on the pharmacokinetics of DABE were also confidently simulated. CONCLUSIONS AND IMPLICATIONS: 'In vivo' [I]/Ki and PBPK modelling, used in combination, can accurately predict P-gp-mediated DDIs. The described framework provides a mechanistic basis for the proper design of clinical DDI studies, as well as avoiding unnecessary clinical DDI studies.

Intestinal absorption and presystemic elimination of various chemical constituents present in GBE50 extract, a standardized extract of Ginkgo biloba leaves.

The nature and level of systemic exposure to the active herbal constituents will profoundly affect their effects at action sites, which is fundamental in understanding their roles in the overall beneficial effects of a herbal medicine. The objective of this study is to gain a full picture of the systemic exposure to various putatively active ginkgo constituents after p.o. administration of GBE50 extract, a standardized extract of Ginkgo biloba leaves, to rats and understanding of the relevant mechanisms governing the intestinal absorption and presystemic elimination. To define the ginkgo compounds to be studied, literature informatics-guided chemical profiling revealed that GBE50 extract contained 72 ginkgo constituents, including terpene lactones, flavonols, flavones, an isoflavone, biflavones, flavanols, and carboxylic acids, at levels ranging from 0.01 to 55.3 mg/g. Among the ginkgo constituent groups were the terpene lactones and the flavonols that were significantly measurable in plasma after p.o. administration of GBE50 extract to rats. The intestinal absorption of terpene lactones appeared to be dictated by their intermediate membrane permeability, while the influences of MDR-1- and MRP-2- mediated intestinal efflux and the presystemic metabolism and biliary excretion might be relatively limited. Because of their deglycosylation absent in the small intestine and relatively slow presystemic elimination, many intact flavonol glycosides appeared in the rat plasma albeit with a limited extent of absorption. Colonic deglycosylation of the flavonol glycosides occurred and the glucuronides of flavonol aglycones were also measured in the plasma. Although some biflavones also had relatively high abundance in GBE50 extract, these ginkgo constituents were not measured in the rat plasma because of their poor solubility and poor permeability that hindered the intestinal absorption. The levels of the remaining ginkgo constituents in GBE50 extract were too low to be measured in the rat plasma. The current study enabled us to better understand the nature of systemic exposure to ginkgo compounds after p.o. administration of GBE50 extract and to more precisely implement multicomponent PK study of the extract.

Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis.

Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1*28 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1*28 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1*28 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1*28 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 genotype (OR=3.69, 95% confidence interval [CI]=2.00-6.83; P<0.001). Considering the patients with a UGT1A1*1/*28 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR=1.92, 95% CI=1.31-2.82; P=0.001). No association was observed between UGT1A1*28 and severe diarrhoea at low doses (<125 mg/m(2)). In conclusion, patients carrying UGT1A1*28 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.

Sex-dependent differences in cytochrome P450 3A activity as assessed by midazolam disposition in humans: a meta-analysis.

Controversy exists concerning the sex-dependent differences in cytochrome P450 3A activity in humans. Meta-analysis of selected studies may address this question. Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans. The following pharmacokinetic parameters were included for the analysis: MDZ oral and systemic clearance, area under the concentration-time curve (AUC) of oral and intravenous MDZ, MDZ oral bioavailability (F), and MDZ gastrointestinal extraction (E(G)). Ten studies including 409 healthy volunteers were identified. Women exhibited 16% higher weight-corrected MDZ oral clearance (P < 0.001) and 20% higher systemic clearance (P = 0.002) than men. No significant difference in the AUC after oral dosing of MDZ was noted between sexes. Women showed lower AUC of intravenous MDZ than men (P = 0.02). No sex-dependent differences were observed in F and E(G). In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed.

Endogenous cortisol 6 beta-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans.

BACKGROUND: We determined if endogenous cortisol 6 beta-hydroxylation clearance [CL(m(6 beta))] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activities). METHODS: In this study, 16 healthy volunteers received a single 7.5 mg oral dose of midazolam (MDZ). Blood samples were drawn up to 24 h after dosing. Urine samples were collected at various time periods after dosing. MDZ, 1-hydroxymidazolam (1-OHMDZ), cortisol (F) and 6 beta-hydroxycortisol (6 beta-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV). RESULTS: CL(m(6 beta)) was poorly correlated (P>0.2) with MDZ oral clearance [CL(oral(MDZ))] and the ratio of AUC(0-infinity(1-OHMDZ)) versus AUC(0-infinity(MDZ)) [MR((AUC))]. However, when examining the data obtained from male volunteers exclusively, strong correlations were observed between CL(m(6 beta)) and CL(oral(MDZ)). Larger interindividual and intraindividual variabilities were observed in urinary ratio of 6 beta-OHF/F compared with CL(m(6 beta)). CONCLUSION: CL(m(6 beta)) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.