The α3ß4 nAChR tissue distribution identified by fluorescent α-conotoxin [D11A]LvIA.

α3ß4, a vital subtype of neuronal nicotinic acetylcholine receptors (nAChRs), is widely distributed in the brain, ganglia, and adrenal glands, associated with addiction and neurological diseases. However, the lack of specific imaging tools for α3ß4 nAChRs has hindered the investigation of their tissue distribution and functions. [D11A]LvIA, a peptide derived from marine cone snails, demonstrates high affinity and potency for α3ß4 nAChRs, making it a valuable pharmacological tool for studying this receptor subtype. In this study, three fluorescent conjugates of [D11A]LvIA were synthesized using 6-TAMRA-SE (R), Cy3-NHS-ester (Cy3), and BODIPY-FL NHS ester (BDP) dyes. The electrophysiological activities were assessed in Xenopus laevis oocytes by two-electrodes voltage clamp (TEVC). [D11A]LvIA-Cy3 and [D11A]LvIA-BDP show improved selectivity and affinity, with IC50 values of 512.70 nM and 343.50 nM, respectively, and [D11A]LvIA-Cy3 exhibits better stability in cerebrospinal fluid (CSF). Utilizing [D11A]LvIA-Cy3, we successfully visualized the distribution of α3ß4 nAChRs in rat trigeminal ganglia, retina, adrenal glands, and various brain regions. This novel fluorescent peptide provides a significant pharmacological tool for the exploration and visualization in-situ distribution of α3ß4 nAChRs in different tissues and also assists in clarifying the function.

Characterization, expression, and polymorphism of MHC II α and MHC II ß in Sichuan taimen (Hucho bleekeri).

The major histocompatibility complex (MHC) is involved in antigen presentation and plays an essential role in regulating immune function. In the present study, we identified two MHC class II genes and investigated their potential roles in Hucho bleekeri. The MHC II α and MHC II ß of H. bleekeri had typical leading peptides, extracellular domains, connecting peptides, transmembrane region, and cytoplasmic region. Amino acid sequence comparison revealed that MHC II of H. bleekeri has high homology with other vertebrates, among which homology with salmonid fish was the highest. Phylogenetic analysis showed that H. bleekeri MHC II clustered with salmonid fish; moreover they clustered with orthologous genes of other fish, whereas mammalian MHC II clustered into a separate branch. Tissue distribution analysis revealed MHC II was widely expressed in all tested tissues, with both MHC II α and MHC II ß highly expressed in the spleen, gill, kidney, and hindgut. After lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly(I:C)) stimulation, the expression of MHC II in the head kidney and spleen of H. bleekeri was significantly upregulated. Compared with MHC II α, MHC II ß acted faster in response to the stimulation. Polymorphism analysis of MHC II revealed that all the different alleles belonged to the same major type, and very limited polymorphisms were found in H. bleekeri MHC II α and II ß. Selection pressure analysis showed signs of weak and non-significant positive selection in the MHC II α and MHC II ß extracellular region. Our study reveals the potential role of MHC II in the immune response of H. bleekeri and provides a reference for studying the evolutionary model of teleost MHC II.

The pharmacokinetics and tissue distribution of curcumin following inhalation administration in rats-A comparative analysis with oral and intravenous routes.

A sensitive and simple method using ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated to determine the concentration of curcumin in rat plasma and tissue samples. Emodin was selected as the internal standard (IS), and biological samples were pretreated with simple one-step acetonitrile precipitation. The calibration curves exhibited linearity within the range of 1-1000 ng/ml for both rat plasma and tissue samples. The accuracy and precision of intra-day as well as inter-day determinations ranged from 99.3% to 117.3% and from 98.2% to 105.1%, respectively. This method demonstrated excellent recovery rates ranging from 76.4% to 96.4% along with minimal matrix effect ranging from 86.5% to 99.6%. The effectiveness of this method was successfully demonstrated through its application in an in vivo pharmacokinetic and tissue distribution study after single administration via inhalation (100 mg/kg), oral gavage (100 mg/kg) and intravenous injection (2.5 mg/kg) of curcumin in rats. The results revealed that inhalation significantly improved the bioavailability of curcumin, with most of the drug being deposited in the lung. These findings highlight inhalation as an effective route for targeted delivery of drugs directly into lung tissues, thus suggesting potential future applications for treating pulmonary diseases utilizing inhaled curcumin.

Uptake, Elimination and Metabolism of Brominated Dibenzofurans in Mice.

Polybrominated dibenzofurans (PBDFs) are major brominated dioxins in the environment, but information on their bioaccumulation potential and toxicokinetics is limited. This study conducted oral exposure experiments with C57BL/6J mice to investigate the uptake ratios, distribution in the liver, plasma and brain, metabolism, and elimination kinetics of four bromine/chlorine-substituted dibenzofurans (TrBDF: 2,3,8-tribromo, TeBDF: 2,3,7,8-tetrabromo, PeBDF: 1,2,3,7,8-pentabromo, TrBCDF: 2,3,7-tribromo-8-chloro) in comparison with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The hepatic uptake ratios of 2,3,7,8-substituted dibenzofurans were lower than that of TCDD (up to 84% of the administered doses) and decreased with the number of Br substitutions (42%, 33%, and 29% for TrBCDF, TeBDF, and PeBDF, respectively). The brain uptake ratios of these dibenzofurans were less than 0.05%, and the plasma-to-brain transfer ratio also decreased with the Br number. All 2,3,7,8-substituted compounds were eliminated from the liver following first-order kinetics, with half-times in the order of TrBCDF (5.6 days) < TeBDF (8.8 days) ≈ TCDD (8.7 days) < PeBDF (13 days). The non-2,3,7,8-substituted TrBDF was poorly retained in the liver (<0.01% of the dose at 1 day) and rapidly eliminated following two-phase kinetics. All dibenzofurans were metabolised into monohydroxylated products in the liver, but the contribution of this metabolic pathway to hepatic elimination was only significant for TrBDF. As the toxic effects of dioxin-like compounds are influenced by their biological persistence, the slow elimination of TrBCDF, TeBDF, and PeBDF observed in this study suggests that exposure risk of brominated dibenzofurans may be underestimated using the toxic equivalency factors of the less persistent chlorinated analogues.

In Vivo Tissue Distribution and Pharmacokinetics of FITC-Labelled Hizikia fusiforme Polyphenol-Polysaccharide Complex in Mice.

In this study, a quantitative method based on fluorescein isothiocyanate (FITC)-labelled Hizikia fusiforme polyphenol-polysaccharide complex (HPC) and its purified fractions (PC1, PC4) was used, and its pharmacokinetics and tissue distribution were investigated in mice. The results showed that the FITC-labelled method had good linearity (R2 > 0.99), intra-day and inter-day precision (RSD, %) consistently lower than 15%, recovery (93.19-106.54%), and stability (RSD < 15%), which met the basic criteria for pharmacokinetic studies. The pharmacokinetic and tissue distribution results in mice after administration showed that all three sample groups could enter the blood circulation. and HPC-FITC had a longer half-life (T1/2: 26.92 ± 0.76 h) and mean retention time (MRT0-∞: 36.48 h) due to its larger molecular weight. The three groups of samples could be absorbed by the organism in a short time (0.5 h) mainly in the stomach and intestine; the samples could be detected in the urine after 2 h of administration indicating strong renal uptake, and faecal excretion reached its maximum at 12 h. The samples were also detected in the urine after 2 h of administration. This study provides some theoretical basis for the tissue distribution pattern of polyphenol-polysaccharide complex.

The ABCG2 Transporter Affects Plasma Levels, Tissue Distribution and Milk Secretion of Lumichrome, a Natural Derivative of Riboflavin.

The ABCG2 membrane transporter affects bioavailability and milk secretion of xenobiotics and natural compounds, including vitamins such as riboflavin. We aimed to characterize the in vitro and in vivo interaction of ABCG2 with lumichrome, the main photodegradation product of riboflavin, which has proven in vitro anti-cancer activity and a therapeutical role in antibacterial photodynamic therapy as an efficient photosensitizer. Using MDCK-II polarized cells overexpressing murine Abcg2 and human ABCG2 we found that lumichrome was efficiently transported by both variants. After lumichrome administration to wild-type and Abcg2-/- mice, plasma AUC20-120 min was 1.8-fold higher in Abcg2-/- mice compared with wild-type mice. The liver and testis from Abcg2-/- mice showed significantly higher lumichrome levels compared with wild-type, whereas lumichrome accumulation in small intestine content of wild-type mice was 2.7-fold higher than in Abcg2-/- counterparts. Finally, a 4.1-fold-higher lumichrome accumulation in milk of wild-type versus Abcg2-/- mice was found. Globally, our results show that ABCG2 plays a crucial role in plasma levels, tissue distribution and milk secretion of lumichrome potentially conditioning its biological activity.

Tissue distribution and temporal and spatial assessment of per- and polyfluoroalkyl substances (PFAS) in smallmouth bass (Micropterus dolomieu) in the mid-Atlantic United States.

Per- and polyfluoroalkyl substances (PFAS) have become an environmental issue worldwide. A first step to assessing potential adverse effects on fish populations is to determine if concentrations of concern are present in a region and if so, in which watersheds. Hence, plasma from adult smallmouth bass Micropterus dolomieu collected at 10 sites within 4 river systems in the mid-Atlantic region of the United States, from 2014 to 2019, was analyzed for 13 PFAS. These analyses were directed at better understanding the presence and associations with land use attributes in an important sportfish. Four substances, PFOS, PFDA, PFUnA, and PFDoA, were detected in every plasma sample, with PFOS having the highest concentrations. Sites with mean plasma concentrations of PFOS below 100 ng/ml had the lowest percentage of developed landcover in the upstream catchments. Sites with moderate plasma concentrations (mean PFOS concentrations between 220 and 240 ng/ml) had low (< 7.0) percentages of developed land use but high (> 30) percentages of agricultural land use. Sites with mean plasma concentrations of PFOS > 350 ng/ml had the highest percentage of developed land use and the highest number PFAS facilities that included military installations and airports. Four of the sites were part of a long-term monitoring project, and PFAS concentrations of samples collected in spring 2017, 2018, and 2019 were compared. Significant annual differences in plasma concentrations were noted that may relate to sources and climatic factors. Samples were also collected at two sites for tissue (plasma, whole blood, liver, gonad, muscle) distribution analyses with an expanded analyte list of 28 PFAS. Relative tissue distributions were not consistent even within one species of similar ages. Although the long-chained legacy PFAS were generally detected more frequently and at higher concentrations, emerging compounds such as 6:2 FTS and GEN X were detected in a variety of tissues.

Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator.

As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood-brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F's pharmacokinetics, warranting further clinical drug-drug interaction (DDI) studies.

In silico assessments of the small molecular boron agents to pave the way for artificial intelligence-based boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a highly targeted, selective and effective technique to cure various types of cancers, with less harm to the healthy cells. In principle, BNCT treatment needs to distribute the 10boron (10B) atoms inside the tumor tissues, selectively and homogeneously, as well as to initiate a nuclear fission reaction by capturing sufficient neutrons which releases high linear energy particles to kill the tumor cells. In BNCT, it is crucial to have high quality boron agents with acceptable bio-selectivity, homogeneous distribution and deliver in required quantity, similar to chemotherapy and other radiotherapy for tumor treatment. Nevertheless, boron drugs currently used in clinical trials yet to meet the full requirements. On the other hand, BNCT processing has opened up the era of renaissance due to the advanced development of the high-quality neutron source and the global construction of new BNCT centers. Consequently, there is an urgent need to use boron agents that have increased biocapacity. Artificial intelligence (AI) tools such as molecular docking and molecular dynamic simulation technologies have been utilized to develop new medicines. In this work, the in silico assessments including bioinformatics assessments of BNCT related tumoral receptor proteins, computational assessments of optimized small molecules of boron agents, are employed to speed up the screening process for boron drugs. The outcomes will be applicable to pave the way for future BNCT that utilizes artificial intelligence. The in silico molecular docking and dynamic simulation results of the optimized small boron agents, such as 4-borono-l-phenylalanine (BPA) with optimized proteins like the L-type amino acid transporter 1 (LTA1, also known as SLC7A5) will be examined. The in silico assessments results will certainly be helpful to researchers in optimizing druggable boron agents for the BNCT application. The clinical status of the optimized proteins, which are highly relevant to cancers that may be treated with BNCT, has been assessed using bioinformatics technology and discussed accordingly. Furthermore, the evaluations of cytotoxicity (IC50), boron uptake and tissue distribution of the optimized ligands 1 and 7 have been presented.

The assessment of pharmacokinetics and neuroprotective effect of berberine hydrochloride-embedded albumin nanoparticles via various administration routes: comparative in-vivo studies in rats.

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles.

Characterization and In vitro Release & In vivo Behavior Study of Self-Assembled Nano-Emulsion in XiaoYao Pill for Enhanced Drug Delivery.

BACKGROUND: Traditional Chinese medicine formulations often contain hydrophobic components with limited solubility and stability, leading to low oral bioavailability. Self-assembled nanoparticles (SANs) have shown promise in enhancing oral bioavailability of these components. However, whether un-decocted Chinese herbal pellets can generate SANs and the impact of SANs formed by multiple components on pharmacokinetic parameters remains unexplored. METHODS: In this study, single-factor approach was employed to determine the optimal separation method of nano-emulsion phase of XiaoYao pill (N-XY). Morphological and particle size analyses confirmed the nanoscale nature of N-XY. High-performance liquid chromatography (HPLC) fingerprint analysis was conducted to compare the distribution of active ingredients among three different phases of XiaoYao pill (XY pill). In vitro release studies were performed to evaluate the release mechanism of four ingredients from N-XY. Additionally, in vivo pharmacokinetics and tissue distribution behaviors were investigated in rats. RESULTS: N-XY exhibited uniform and stable characteristics as a water-in-oil (O/W) nano-emulsion. Fingerprint analysis identified 25 characteristic peaks and 8 key ingredients in N-XY, with the highest peak areas. In vitro release studies showed a sustained release behavior of N-XY. The pharmacokinetics study showed that the ferulic acid of N-XY had a 1.37-fold higher AUC, 1.44-fold lower Vd/F, 1.39-fold lower CL/F, and a prolonged t1/2 than A-XY, indicating enhanced bioavailability due to reduced elimination. Furthermore, the tissue distribution revealed that the levels of paeoniflorin and ferulic acid from N-XY significantly increased in liver, spleen, lungs, uterus and ovaries, exhibiting targeting characteristics. CONCLUSION: This study comprehensively explored the formation, characterization, and pharmacokinetics of nano-emulsion in XY pill, introducing novel perspectives and initiating preliminary research on potential SANs in un-decocted traditional Chinese medicine formulations. It also emphasized the importance of enhancing pharmacokinetics of hydrophobic components in Chinese herbal formulations and laid the foundation for future nano-formulation research for XY pill.

Design and evaluation of a drug-in-adhesive patch for the transdermal delivery of ketoprofen.

The purpose of this study was to design a drug-in-adhesive (DIA) patch for transdermal delivery of ketoprofen, using hot-melt pressure-sensitive adhesive as the matrix of the patch. The adhesion properties and skin permeation of the patches were examined, and in vivo pharmacokinetics and tissue distribution of patches were evaluated. The novel ketoprofen patch with high adhesion was prepared by holt-melt method. The effects of different percentages of L-menthol on in vitro permeation were screened, 3% was added as the amount of permeation enhancer and the 24 h cumulative permeation amount(277.46 ± 15.58 µg/cm2) comparable to that of commercial patch MOHRUS®(279.74 ± 29.23 µg/cm2). Pharmacokinetic and the tissue distribution study showed no matter in plasma, muscle or skin, the drug concentration of self-made ketoprofen patch was equivalent to that of commercial patch. These data indicated that the self-made patch provided a new reference for the development of ketoprofen dosage forms and promising alternative strategy for analgesic treatment.

A UPLC-MS/MS coupled with GC-MS method for quantification of twenty-one chemical ingredients from Suxiao Jiuxin pill in multiple tissue of rat and its application to tissue distribution study.

Suxiao Jiuxin pill (SJP) was a commonly-used traditional Chinese medicine for treating cardiovascular diseases. It was composed of the rhizome of Ligusticum chuanxiong Hort. and Borneolum Syntheticum. The distribution of SJP in vivo was still ambiguous. A UPLC-MS/MS coupled with GC-MS method was developed to quantify twenty-one chemical ingredients in multiple tissues from rat after administration of SJP. Protein precipitation and liquid-liquid microextraction were both utilized in sample pretreatment. All analytes were detected under acceptable specificity, linearity (correlation coefficient > 0.992), sensitivity (LLOQ < 12.5 ng/mL), precision (RSD < 14.8 %), accuracy (RE < ±14.6 %), extraction recovery (between 52.8 % and 124.1 %), matrix effect (ranged from 60.5 % and 149.7 %) and stability (RE < ±16.0 %). The established method was successfully applied in the tissue distribution study of SJP in rats. As a result, the distribution characteristics of ten analytes were clearly elucidated, including borneol, isoborneol, ligustilide, senkyunolide A, ferulic acid, senkyunolide I, levistolide A, neocnidilide, senkyunolide H and angelicide. The information provided by this research was greatly meaningful for the active chemical ingredient exploration and clinical application of SJP.

Cell-penetrating peptides TAT and 8R functionalize P22 virus-like particles to enhance tissue distribution and retention in vivo.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

Spatial Metabolomic Profiling of Pinelliae Rhizoma from Different Leaf Types Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging.

Pinelliae Rhizoma (PR), a highly esteemed traditional Chinese medicinal herb, is widely applied in clinical settings due to its diverse pharmacological effects, including antitussive, expectorant, antiemetic, sedative-hypnotic, and antitumor activities. Pinellia ternata exhibits morphological variation in its leaves, with types resembling peach, bamboo, and willow leaves. However, the chemical composition differences among the corresponding rhizomes of these leaf phenotypes remain unelucidated. This pioneering research employed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) to conduct the in situ identification and spatial profiling of 35 PR metabolites in PR, comprising 12 alkaloids, 4 organic acids, 12 amino acids, 5 flavonoids, 1 sterol, and 1 anthraquinone. Our findings revealed distinct spatial distribution patterns of secondary metabolites within the rhizome tissues of varying leaf types. Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) effectively differentiated between rhizomes associated with different leaf morphologies. Furthermore, this study identified five potential differential biomarkers-methylophiopogonanone B, inosine, cytidine, adenine, and leucine/isoleucine-that elucidate the biochemical distinctions among leaf types. The precise tissue-specific localization of these secondary metabolites offers compelling insights into the specialized accumulation of bioactive compounds in medicinal plants, thereby enhancing our comprehension of PR's therapeutic potential.

[Comparison on tissue distribution of five components in Shuganning Injection and Scutellariae Radix extract by UPLC-MS/MS].

This study established an ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method to determine the content of five index components in rat tissues and organs after administration of Shuganning Injection or Scutellariae Radix extract. The dynamic changes and differences of the distribution of the five index components over time between the two groups were studied, and the effects of Scutellariae Radix alone or in combination with other medicines on the tissue distribution of the five components were explored. After Shuganning Injection or Scutellariae Radix extract was injected into the tail vein of rats, the heart, liver, spleen, lung, kidney, stomach, intestine, and brain tissue samples were collected at four time points of 0.17, 0.5, 1, and 2 h, respectively. UPLC-MS/MS was employed to measure the concentrations of the five index components(baicalin, baicalein, oroxylin A, oroxylin A-7-O-ß-D-glucuronide, and scutellarin) in the samples of the two groups. The results showed that the established method was simple, fast, and exclusively stable. After the administration of Shuganning Injection and Scutellariae Radix extract, the five index components presented wide distribution and had differences in vivo. The two groups showcased abundant distribution of baicalin, baicalein, and oroxylin A in the kidney and liver, oroxylin A-7-O-ß-D-glucuronide in the kidney and brain, and scutellarin in the kidney and heart. The content of baicalin in the heart, liver, kidney, and intestine, baicalein in the liver and kidney, and oroxylin A in the lung after administration of Shuganning Injection(Scutellariae Radix in combination with other medicines) was significantly higher than that after administration of Scutellariae Radix extract. The results of this study suggested that the five components of Shuganning Injection and Scutellariae Radix extract demonstrated wide distribution without accumulation in rats. The combination of Scutellariae Radix with other medicines can increase the distribution of active components in rats, which provided a basis for explaining the rationality of the compatibility of Shuganning Injection from in vivo processes.

Accumulation of Parabens, Their Metabolites, and Halogenated Byproducts in Migratory Birds of Prey: A Comparative Study in Texas and North Carolina, USA.

Parabens are alkyl esters of p-hydroxybenzoic acid that are commonly used as preservatives in personal care products such as cosmetics. Recent studies have revealed the presence of parabens in surface and tap water because of their use as disinfection products; however, little is known about their occurrence in biological samples and their bioaccumulation potential, particularly in raptor birds known as sentinels for pollutant detection. We examined the occurrence and tissue distribution of parabens, their metabolites, and halogenated byproducts in the liver, kidney, brain, and muscle of birds of prey from Texas and North Carolina (USA). Methylparaben (MeP), propylparaben (PrP), and butylparaben (BuP) were detected in more than 50% of all tissues examined, with the kidney exhibiting the highest concentration of MeP (0.65-6.84 ng/g wet wt). Para-hydroxybenzoic acid (PHBA), a primary metabolite, had the highest detection frequency (>50%) and a high accumulation range in the liver, of 4.64 to 12.55 ng/g. The chlorinated compounds chloromethylparaben and chloroethylparaben were found in over half of the tissues, of which dichloromethylparaben (2.20-3.99 ng/g) and dichloroethylparaben (1.01-5.95 ng/g) in the kidney exhibited the highest concentrations. The dibrominated derivatives dibromideethylparaben (Br2EtP) was detected in more than 50% of samples, particularly in muscle and brain. Concentrations in the range of 0.14 to 17.38 ng/g of Br2EtP were detected in the kidney. Dibromidepropylparaben (Br2PrP) was not frequently detected, but concentrations ranged from 0.09 to 21.70 ng/g in muscle. The accumulations of total amounts (sum) of parent parabens (∑P), metabolites (∑M), and halogenated byproducts (∑H) in different species were not significantly different, but their distribution in tissues differed among the species. Positive correlations were observed among MeP, PrP, BuP, and PHBA in the liver, suggesting similar origins and metabolic pathways. Environ Toxicol Chem 2024;43:2365-2376. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Machine Learning Prediction of On/Off Target-driven Clinical Adverse Events.

OBJECTIVE: Currently, 90% of clinical drug development fails, where 30% of these failures are due to clinical toxicity. The current extensive animal toxicity studies are not predictive of clinical adverse events (AEs) at clinical doses, while current computation models only consider very few factors with limited success in clinical toxicity prediction. We aimed to address these issues by developing a machine learning (ML) model to directly predict clinical AEs. METHODS: Using a dataset with 759 FDA-approved drugs with known AEs, we first adapted the ConPLex ML model to predict IC 50 values of these FDA-approved drugs against their on-target and off-target binding among 477 protein targets. Subsequently, we constructed a new ML model to predict clinical AEs using IC 50 values of 759 drugs' primary on-target and off-target effects along with tissue-specific protein expression profiles. RESULTS: The adapted ConPLex model predicted drug-target interactions for both on- and off-target effects, as shown by co-localization of the 6 small molecule kinase inhibitors with their respective kinases. The coupled ML models demonstrated good predictive capability of clinical AEs, with accuracy over 75%. CONCLUSIONS: Our approach provides a new insight into the mechanistic understanding of in vivo drug toxicity in relationship with drug on-/off-target interactions. The coupled ML models, once validated with larger datasets, may offer advantages to directly predict clinical AEs using in vitro/ex vivo and preclinical data, which will help to reduce drug development failure due to clinical toxicity.

Vitamin D beyond the blood: Tissue distribution of vitamin D metabolites after supplementation.

Vitamin D3's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D3, is well characterized. However, the increasing recognition of vitamin D3's paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D3 levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D3 in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D3, and the primary clearance metabolite, 24,25-dihydroxyvitamin D3. While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D3 needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D3 and its metabolites are retained in tissues selectively. Notably, vitamin D3 concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D3 levels may not adequately reflect vitamin D3 and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D3 and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D3's cellular effects and guide refinement of clinical trial methodologies.

Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice.

Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by Streptomyces spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (t1/2), area under the curve (AUC) and peak concentration (Cmax) values of tralopyril were significantly higher than those of chlorfenapyr (P < 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood-brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC-MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.