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European Journal of Pharmaceutical... Aug 2022The organic anion transporter 1 (OAT1) is mainly expressed in proximal tubule cells, where it mediates the renal uptake of endogenous and exogenous compounds. Thereby,...
The organic anion transporter 1 (OAT1) is mainly expressed in proximal tubule cells, where it mediates the renal uptake of endogenous and exogenous compounds. Thereby, it has enormous clinical relevance particularly in drug-drug interactions. The aim of the present in vitro study was to elucidate potential species dependent disparity of human and mouse OAT1 in handling of structural diverse drugs and pesticides. A basic functional comparison of the two transporters showed a similar time-dependent uptake of the substrate para-aminohippuric acid (PAH), the affinity (K) was 94 µM for hOAT1 and 32 µM for mOat1. Inhibition experiments for hOAT1 and mOat1 provided IC values for glibenclamide of 5.1 and 6.4 µM and for probenecid of 31 and 11 µM. Than the interaction of hOAT1 and mOat1 with 23 drugs and 13 pesticides was examined. Three pesticides and thirteen drugs showed high inhibitory potency of 50% or more to both transporters. Furthermore, we identified rosiglitazone as a differential active inhibitor, with stronger inhibitory properties (IC) to mOat1 (7.7 µM) than to hOAT1 (31 µM), and olmesartan with the most pronounced difference: The IC of hOAT1 (0.40 µM) was 48-fold lower than of mOat1 (19 µM). In conclusion, we found a strong correlation for the inhibitory effects of most drugs and pesticides on human and mouse OAT1. But the example of olmesartan shows that species differences have to be considered when extrapolating data from mouse to human.
Topics: Animals; Biological Transport; Humans; Kidney; Membrane Transport Proteins; Mice; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent; Pesticides
PubMed: 35644507
DOI: 10.1016/j.ejps.2022.106217 -
Antimicrobial Agents and Chemotherapy Jun 2022Mycobacteroides abscessus () is an emerging environmental microbe that causes chronic lung disease in patients with compromised lung function such as cystic fibrosis and...
Mycobacteroides abscessus () is an emerging environmental microbe that causes chronic lung disease in patients with compromised lung function such as cystic fibrosis and bronchiectasis. It is intrinsically resistant to most antibiotics, therefore there are only few antibiotics that can be repurposed to treat disease. Although current recommendations require daily intake of multiple antibiotics for more than a year, cure rate is low and often associated with significant adverse events. Here, we describe efficacy of T405, a recently discovered β-lactam antibiotic of the penem subclass, in a mouse model of pulmonary infection. Imipenem, one of the standard-of-care drugs to treat disease, and also a β-lactam antibiotic from a chemical class similar to T405, was included as a comparator. Probenecid was included with both T405 and imipenem to reduce the rate of their renal clearance. T405 exhibited bactericidal activity against from the onset of treatment and reduced lung burden at a rate similar to that exhibited by imipenem. The MIC of T405 against was unaltered after 4 weeks of exposure to T405 in the lungs of mice. Using an assay, we also demonstrate that T405 in combination with imipenem, cefditoren or avibactam exhibits synergism against . Additionally, we describe a scheme for synthesis and purification of T405 on an industrial scale. These attributes make T405 a promising candidate for further preclinical assessment to treat disease.
Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Humans; Imipenem; Meropenem; Mice; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; beta-Lactams
PubMed: 35638855
DOI: 10.1128/aac.00536-22 -
Viruses Apr 2022RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an...
RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.
Topics: Animals; COVID-19; Mice; Probenecid; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; SARS-CoV-2; Virus Replication
PubMed: 35632652
DOI: 10.3390/v14050912 -
Journal of Enzyme Inhibition and... Dec 2022Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these...
Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these moieties, we herein present the synthesis, single-crystal X-ray analysis, DFT studies, and -amylase inhibition of probenecid derived two -alkylphthalimide-oxadiazole-benzenesulfonamide hybrids. The synthesis has been accomplished in high yields. The final structures of both hybrids have been established completely with the help of different spectro-analytical techniques, including NMR, FTIR, HR-MS, and single-crystal X-ray diffraction analyses. In an effort to confirm the experimental findings, versatile quantum mechanical calculations and Hirshfeld Surface analysis have been performed. -Amylase inhibition assay has been executed to investigate the enzyme inhibitory potential of both hybrids. The low IC value (76.92 ± 0.19 μg/mL) of hybrid shows the good -amylase inhibition potential of the respective compound. Ultimately, the binding affinities and features of the two hybrids are elucidated utilising a molecular docking technique against the -amylase enzyme.
Topics: Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Probenecid; Sulfonamides; X-Ray Diffraction; alpha-Amylases; Benzenesulfonamides
PubMed: 35616297
DOI: 10.1080/14756366.2022.2078969 -
Organometallics Apr 2022Quantitative catalytic nucleophilic fluorination of a range of acyl chlorides to acyl fluorides was promoted by a cyclometallated rhodium complex...
Quantitative catalytic nucleophilic fluorination of a range of acyl chlorides to acyl fluorides was promoted by a cyclometallated rhodium complex [(η,κC-CMeCHCFCHNCHNMe)- RhCl] (). can be prepared in high yields from commercially available starting materials using a one-pot method. The catalyst could be separated, regenerated, and reused. Rapid quantitative fluorination generated the fluoride analogue of the active pharmaceutical ingredient probenecid. Infrared in situ monitoring verified the clean conversion of the substrates to products. VTNA graphical kinetic analysis and DFT calculations lead to a postulated reaction mechanism involving a nucleophilic Rh-F bond.
PubMed: 35571260
DOI: 10.1021/acs.organomet.2c00052 -
Plants (Basel, Switzerland) May 2022Glycyrrhizin (GL), a triterpene compound produced by species, is a crucial pharmacologically active component of crude drugs. In contrast to the biosynthesis of GL in...
Glycyrrhizin (GL), a triterpene compound produced by species, is a crucial pharmacologically active component of crude drugs. In contrast to the biosynthesis of GL in plants, little is known about GL transport and accumulation in plants. The transport mechanism of GL was characterized using cultured cells of . Cultured cells of efficiently incorporated exogenously supplied GL. Proton pump inhibitors, such as probenecid and niflumic acid, as well as a protonophore (carbonylcyanide -chlorophenylhydrazone), markedly inhibited GL uptake by cultured cells, whereas vanadate exhibited a moderate inhibition. Furthermore, GL transport by tonoplast vesicles is dependent not on a H-electrochemical gradient but MgATP and is markedly inhibited by vanadate. These results suggest that GL uptake by cultured cells is mediated by a H-symporter in the plasma membrane and an ATP-binding cassette transporter, which has high specificity for the aglycone structure of GL on the tonoplast.
PubMed: 35567251
DOI: 10.3390/plants11091250 -
International Journal of Molecular... Apr 2022The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson's disease, as well as in neuropathic pain. These...
The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson's disease, as well as in neuropathic pain. These observations make Panx-1 an interesting biological target. We previously published some potent indole derivatives as Panx-1 blockers, and as continuation of the research in this field we report here the studies on additional chemical scaffolds, naphthalene and pyrazole, appropriately substituted with those functions that gave the best results as in our indole series (sulphonamide functions and one/two carboxylic groups) and in Panx-1 blockers reported in the literature (sulphonic acid). Compounds and , the latter being an analogue of the drug Probenecid, are the most potent Panx-1 blockers obtained in this study, with I = 97% and I = 93.7% at 50 µM, respectively. Both compounds, tested in a mouse model of oxaliplatin-induced neuropathic pain, showed a similar anti-hypersensitivity profile and are able to significantly increase the mouse pain threshold 45 min after the injection of the doses of 1 nmol and 3 nmol. Finally, the molecular dynamic studies and the PCA analysis have made it possible to identify a discriminating factor able to separate active compounds from inactive ones.
Topics: Animals; Connexins; Indoles; Mice; Molecular Dynamics Simulation; Neuralgia; Probenecid
PubMed: 35563213
DOI: 10.3390/ijms23094827 -
Clinical Pharmacology and Therapeutics Sep 2022Probenecid is used to treat gout and hyperuricemia as well as increase plasma levels of antiviral drugs and antibiotics. In vivo, probenecid mainly inhibits the renal...
Probenecid is used to treat gout and hyperuricemia as well as increase plasma levels of antiviral drugs and antibiotics. In vivo, probenecid mainly inhibits the renal SLC22 organic anion transporters OAT1 (SLC22A6), OAT3 (SLC22A8), and URAT1 (SLC22A12). To understand the endogenous role of these transporters in humans, we administered probenecid to 20 healthy participants and metabolically profiled the plasma and urine before and after dosage. Hundreds of metabolites were significantly altered, indicating numerous drug-metabolite interactions. We focused on potential OAT1 substrates by identifying 97 metabolites that were significantly elevated in the plasma and decreased in the urine, indicating OAT-mediated clearance. These included signaling molecules, antioxidants, and gut microbiome products. In contrast, urate was the only metabolite significantly decreased in the plasma and elevated in the urine, consistent with an effect on renal reuptake by URAT1. Additional support comes from metabolomics analyses of our Oat1 and Oat3 knockout mice, where over 50% of the metabolites that were likely OAT substrates in humans were elevated in the serum of the mice. Fifteen of these compounds were elevated in both knockout mice, whereas six were exclusive to the Oat1 knockout and 4 to the Oat3 knockout. These may be endogenous biomarkers of OAT function. We also propose a probenecid stress test to evaluate kidney proximal tubule organic anion transport function in kidney disease. Consistent with the Remote Sensing and Signaling Theory, the profound changes in metabolite levels following probenecid treatment support the view that SLC22 transporters are hubs in the regulation of systemic human metabolism.
Topics: Animals; Anions; Humans; Kidney; Mice; Mice, Knockout; Organic Anion Transport Protein 1; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Organic Cation Transport Proteins; Probenecid
PubMed: 35490380
DOI: 10.1002/cpt.2630 -
Methods in Molecular Biology (Clifton,... 2022Taxoids such as paclitaxel (Taxol) are an important class of anticancer drugs that bind β-tubulin and stabilize cellular microtubules. To provide new chemical tools for...
Taxoids such as paclitaxel (Taxol) are an important class of anticancer drugs that bind β-tubulin and stabilize cellular microtubules. To provide new chemical tools for studies of microtubules, we synthesized derivatives of paclitaxel modified at the 7-position with the small coumarin-derived fluorophore Pacific Blue (PB). Three of these Pacific Blue-Taxoids termed PB-Gly-Taxol, PB-β-Ala-Taxol, and PB-GABA-Taxol bind purified crosslinked microtubules with affinities of 34-265 nM, where the affinity can be tuned based on the length of an amino acid linker. When added to living cells in the presence of verapamil or probenecid as inhibitors of efflux, these compounds allow visualization of the microtubule network by confocal microscopy. We describe methods for the synthesis of these probes, determination of their affinities for crosslinked tubulin, and imaging of microtubules in living HeLa cells. We further describe their uptake by Caco-2 cells and two transporter-deficient Caco-2 knockout cell lines in the absence and presence of efflux inhibitors by flow cytometry. These studies revealed that p-glycoprotein (MDR1) and multidrug-resistance protein 2 (MRP2) are major mediators of efflux of these molecular probes. These compounds provide useful tools for studies of microtubules and cellular efflux transporters in living cells.
Topics: Caco-2 Cells; Fluorescent Dyes; HeLa Cells; Humans; Microtubules; Molecular Probes; Paclitaxel; Taxoids; Tubulin
PubMed: 35476349
DOI: 10.1007/978-1-0716-1983-4_28 -
Communicable Diseases Intelligence... Apr 2022The National Neisseria Network (NNN), Australia, comprises reference laboratories in each state and territory established in 1979. The NNN has reported data on...
The National Neisseria Network (NNN), Australia, comprises reference laboratories in each state and territory established in 1979. The NNN has reported data on susceptibility profiles for all Neisseria gonorrhoeae isolated from each jurisdiction for an agreed group of antimicrobial agents for the Australian Gonococcal Surveillance Programme (AGSP) since 1981. The antibiotics reported represent current or potential agents used for the treatment of gonorrhoea and include ceftriaxone; azithromycin; ciprofloxacin; and penicillin. More recently, gentamicin susceptibilities are included in the AGSP Annual Report. Ceftriaxone, combined with azithromycin, is the recommended treatment regimen for gonorrhoea in the majority of Australia. However, there are substantial geographic differences in susceptibility patterns in Australia, with certain remote regions of the Northern Territory and Western Australia having low gonococcal antimicrobial resistance rates. In these regions, an oral treatment regimen comprising amoxycillin, probenecid, and azithromycin is recommended for the treatment of gonorrhoea.
Topics: Azithromycin; Ceftriaxone; Gonorrhea; Humans; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Northern Territory
PubMed: 35469554
DOI: 10.33321/cdi.2022.46.19