Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Tu Y
PROVIDER: S-EPMC8248983 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In modeling blood-brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.
| S-EPMC3496430 | biostudies-literature
Project description:Few investigations have been conducted on the disposition and fate of silver nanoparticles (AgNP) in pregnancy. The distribution of a single dose of polyvinylpyrrolidone (PVP)-stabilized AgNP was investigated in pregnant rats. Two sizes of AgNP, 20 and 110?nm, and silver acetate (AgAc) were used to investigate the role of AgNP diameter and particle dissolution in tissue distribution, internal dose and persistence. Dams were administered AgNP or AgAc intravenously (i.v.) (1?mg?kg-1 ) or by gavage (p.o.) (10?mg?kg-1 ), or vehicle alone, on gestation day 18 and euthanized at 24 or 48?h post-exposure. The silver concentration in tissues was measured using inductively-coupled plasma mass spectrometry. The distribution of silver in dams was influenced by route of administration and AgNP size. The highest concentration of silver (?g Ag g-1 tissue) at 48?h was found in the spleen for i.v. administered AgNP, and in the lungs for AgAc. At 48?h after p.o. administration of AgNP, the highest concentration was measured in the cecum and large intestine, and for AgAc in the placenta. Silver was detected in placenta and fetuses for all groups. Markers of cardiovascular injury, oxidative stress marker, cytokines and chemokines were not significantly elevated in exposed dams compared to vehicle-dosed control. NMR metabolomics analysis of urine indicated that AgNP and AgAc exposure impact the carbohydrate, and amino acid metabolism. This study demonstrates that silver crosses the placenta and is transferred to the fetus regardless of the form of silver. Copyright © 2016 John Wiley & Sons, Ltd.
| S-EPMC5373957 | biostudies-literature
Project description:Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.
| S-EPMC8224427 | biostudies-literature
Project description:Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a four-site perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo.
| S-EPMC4406953 | biostudies-literature
Project description:Phenethyl isothiocyanate (PEITC) is a constituent of cruciferous vegetables that has demonstrated cancer preventive activity in a number of cancer models including lung, prostate, and breast cancer. Our objective was to examine the effects of the oral administration of PEITC for 7 days on the hepatic expression of genes important in drug metabolism and toxicity in Sprague Dawley rats. The liver is the major site for the metabolism of various xenobiotics and carcinogens, and determining the effects of PEITC on the gene expression of hepatic enzymes may provide insight into mechanisms underlying the cancer preventive activity of PEITC.Using a microarray containing 282 genes, we observed that PEITC significantly up-regulated UDP-glucuronosyltransferase UGT1A6 and strongly down-regulated nicotinamide N-methyltransferase (NNMT). We also confirmed the down-regulation of NNMT by real-time quantitative RT-PCR. Other genes that were significantly up-regulated were the drug metabolizing enzyme cyp2b15, the anti-apoptotic gene bcl2l2, and the stress regulators Gadd45b, Dnajb9, Dnajb5 and Hspb1.Our results indicate new targets that may be important in the mechanisms of the anticancer effects of PEITC. Of particular significance was the down-regulation of NNMT which may represent a new target for the treatment of a variety of cancers.
| S-EPMC3017723 | biostudies-literature
Project description:Intestinal microbiota has been extensively studied in the context of host health benefit, and it has recently become clear that the gut microbiota influences drug pharmacokinetics and correspondingly efficacy. Intestinal microbiota dysbiosis is closely related with liver cirrhosis, especially the depletion of Lactobacillus. Therefore, the bioavailability of orally administered glycyrrhizic acid (GL) was speculated to be influenced under a pathological state. In the present study, L. murinus was isolated and screened for GL bioconversion capacity in vitro. Compared with Lactobacillus rhamnosus and Lactobacillus acidophilus, L. murinus was chosen for further investigation because it has the highest biotransformation rate. Our results showed that L. murinus could significantly improve the translocation of GL on Caco-2 cell models. Meanwhile, L. murinus was observed to have the ability to bind with the surface of Caco-2 cells and prominently downregulate the transporter gene expression level of multidrug resistance gene 1 (MDR1) and multidrug resistance protein 2 (MRP2), which were involved in the efflux of drugs. Furthermore, L. murinus was selected to be orally administred into rats in healthy and liver cirrhosis groups by a daily gavage protocol. Our data highlighted that supplements of L. murinus significantly improved the bioavailability of orally administered GL in rats, especially under a pathological condition, which may provide a novel strategy for improving the clinical therapeutic effect of liver protective drugs.
| S-EPMC7193032 | biostudies-literature
Project description:Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects; we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMN▵7), and in juvenile Wistar Hanover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies.
| S-EPMC8565466 | biostudies-literature
Project description:One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.
| S-EPMC6955864 | biostudies-literature
Project description:PCBs, such as PCB3, are air contaminants in buildings and outdoors. Metabolites of PCB3 are potential endocrine disrupting chemicals and genotoxic agents. We studied the disposition of phenolic and sulfated metabolites after acute nose-only inhalation exposure to airborne PCB3 for 2 h in female rats. Inhalation exposure was carried out in three groups. In the first group, rats exposed to an estimated dose of 26 μg/rat were euthanized at 0, 1, 2, and 4 h after exposure. Highest concentrations of phenols and sulfates were observed at 0 h, and the values were 7 ± 1 and 560 ± 60 ng/mL in serum, 213 ± 120 and 842 ± 80 ng/g in liver, 31 ± 27 and 22 ± 7 ng/g in lung, and 27 ± 6 and 3 ± 0 ng/g in brain, respectively. First-order serum clearance half-lives of 0.5 h for phenols and 1 h for sulfates were estimated. In the second group, rats exposed to an estimated dose of 35 μg/rat were transferred to metabolism cages immediately after exposure for the collection of urine and feces over 24 h. Approximately 45 ± 5% of the dose was recovered from urine and consisted mostly of sulfates; the 18 ± 5% of the dose recovered from feces was exclusively phenols. Unchanged PCB3 was detected in both urine and feces but accounted for only 5 ± 3% of the dose. Peak excretion of metabolites in both urine and feces occurred within 18 h postexposure. In the third group, three bile-cannulated rats exposed to an estimated dose of 277 μg/rat were used for bile collection. Bile was collected for 4 h immediately after 2 h exposure. Biliary metabolites consisted mostly of sulfates, some glucuronides, and lower amounts of the free phenols. Control rats in each group were exposed to clean air. Clinical serum chemistry values, serum T4 level, and urinary 8-hydroxy-2'-deoxyguanosine were similar in treated and control rats. These data show that PCB3 is rapidly metabolized to phenols and conjugated to sulfates after inhalation and that both of these metabolites are distributed to liver, lungs, and brain. The sulfates elaborated into bile are either reabsorbed or hydrolyzed in the intestine and excreted in the feces as phenols.
| S-EPMC4137987 | biostudies-literature
Project description:The compound 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), a replacement for perfluorooctanesulfonate (PFOS) in the electroplating industry, has been widely detected in numerous environmental matrices, human sera, and organisms. Due to regulations that limit PFOS use, F-53B use is expected to increase. Therefore, in this study, we performed a subchronic oral toxicity study of F-53B in Sprague Dawley (SD) rats. F-53B was administered orally once daily to male and female rats for 28 days at doses of 5, 20, and 100 mg/kg/day. There were no toxicologically significant changes in F-53B-treated rats, except in the thyroid gland. However, F-53B slightly reduced the serum concentrations of thyroid hormones, including triiodothyronine and thyroxine, compared with their concentrations in the vehicle group. F-53B also induced follicular hyperplasia and was associated with increased thyroid hormone biosynthesis-associated protein expression. These results demonstrate that F-53B is a strong regulator of thyroid hormones in SD rats as it disrupts thyroid function. Thus, caution should be exercised in the industrial application of F-53B as an alternative for PFOS.
| S-EPMC7560397 | biostudies-literature