544 results match your criteria presence probenecid

Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid.

Br J Clin Pharmacol 2021 May 7. Epub 2021 May 7.

Department of Infectious Diseases, Christchurch Hospital, Christchurch, New Zealand.

Aim: Oral flucloxacillin may be co-administered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination.

Methods: We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Read More

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Transient receptor potential vanilloid 2 mediates the inhibitory effect of far-infrared irradiation on adipogenic differentiation of tonsil-derived mesenchymal stem cells.

Stem Cell Res 2021 Mar 17;53:102291. Epub 2021 Mar 17.

Department of Molecular Medicine, College of Medicine, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul 07804, Republic of Korea; Graduate Program in System Health Science and Engineering, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul 07804, Republic of Korea. Electronic address:

Aims: Far-infrared (FIR) irradiation inhibits adipogenic differentiation of tonsil-derived mesenchymal stem cells (TMSCs) by activating Ca-dependent protein phosphatase 2B (PP2B), but it stimulates osteogenic differentiation in a PP2B-independent pathway. We investigated the potential involvement of transient receptor potential vanilloid (TRPV) channels, a well-known Ca-permeable channel, in the effects of FIR irradiation on adipogenic or osteogenic differentiation of TMSCs.

Methods: TMSCs, in the absence or presence of activators or inhibitors, were exposed to FIR irradiation followed by adipogenic or osteogenic differentiation, which was assessed using Oil red O or Alizarin red S staining, respectively. Read More

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Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters.

CPT Pharmacometrics Syst Pharmacol 2021 Mar 11. Epub 2021 Mar 11.

Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK.

Renal clearance of many drugs is mediated by renal organic anion transporters OAT1/3 and inhibition of these transporters may lead to drug-drug interactions (DDIs). Pyridoxic acid (PDA) and homovanillic acid (HVA) were indicated as potential biomarkers of OAT1/3. The objective of this study was to develop a population pharmacokinetic model for PDA and HVA to support biomarker qualification. Read More

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Novel Pannexin-1-Coupled Signaling Cascade Involved in the Control of Endothelial Cell Function and NO-Dependent Relaxation.

Oxid Med Cell Longev 2021 20;2021:2678134. Epub 2021 Feb 20.

Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile.

Deletion of pannexin-1 (Panx-1) leads not only to a reduction in endothelium-derived hyperpolarization but also to an increase in NO-mediated vasodilation. Therefore, we evaluated the participation of Panx-1-formed channels in the control of membrane potential and [Ca] of endothelial cells. Changes in NO-mediated vasodilation, membrane potential, superoxide anion (O) formation, and endothelial cell [Ca] were analyzed in rat isolated mesenteric arterial beds and primary cultures of mesenteric endothelial cells. Read More

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February 2021

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator.

Drug Metab Dispos 2021 May 25;49(5):389-394. Epub 2021 Feb 25.

Novartis Institutes for Biomedical Research, Basel, Switzerland (H.M.W., T.L., G.R., and B.P.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (M.C.); Novartis Institutes for Biomedical Research, East Hanover, New Jersey (S.K. and B.S.); and Novartis Healthcare Pvt. Ltd., Hyderabad, India (J.V.).

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Read More

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Capillaries communicate with the arteriolar microvascular network by a pannexin/purinergic-dependent pathway in hamster skeletal muscle.

Am J Physiol Heart Circ Physiol 2021 04 19;320(4):H1699-H1711. Epub 2021 Feb 19.

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.

We sought to determine if a pannexin/purinergic-dependent intravascular communication pathway exists in skeletal muscle microvasculature that facilitates capillary communication with upstream arterioles that control their perfusion. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries and observed the vasodilatory response in the associated upstream 4A arteriole. We stimulated capillaries with vasodilators relevant to muscle contraction: 10 M -nitroso--acetyl-dl-penicillamine (SNAP; nitric oxide donor), 10 M adenosine, 10 mM potassium chloride, 10 M pinacidil, as well as a known initiator of gap-junction-dependent intravascular communication, acetylcholine (10 M), in the absence and the presence of the purinergic membrane receptor blocker suramin (10 M), pannexin blocker mefloquine (2 × 10 M), or probenecid (5 × 10 M) and gap-junction inhibitor halothane (0. Read More

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Microphysiological system modeling of ochratoxin A-associated nephrotoxicity.

Toxicology 2020 11 6;444:152582. Epub 2020 Sep 6.

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, 98195, USA; Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98104, USA. Electronic address:

Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic, and immunotoxic properties. Specifically, a major concern is severe nephrotoxicity, which is characterized by degeneration of epithelial cells of the proximal tubules and interstitial fibrosis. However, the mechanism of OTA toxicity, as well as the genetic risk factors contributing to its toxicity in humans has been elusive due to the lack of adequate models that fully recapitulate human kidney function in vitro. Read More

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November 2020

Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib.

Pharmaceutics 2020 Aug 20;12(9). Epub 2020 Aug 20.

Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands.

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Read More

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Organic anion transporters also mediate the drug-drug interaction between imipenem and cilastatin.

Asian J Pharm Sci 2020 Mar 28;15(2):252-263. Epub 2018 Dec 28.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.

This study aimed to clarify that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between imipenem and cilastatin. After co-administration with imipenem, the plasma concentrations and the plasma concentration-time curve () of cilastatin were significantly increased, while renal clearance and cumulative urinary excretion of cilastatin were decreased. At the same time, imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1 (hOAT1)-HEK293 and human OAT3 (hOAT3)-HEK293 cells. Read More

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Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1.

Biomolecules 2020 04 9;10(4). Epub 2020 Apr 9.

Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico "Dr. Eduardo Liceaga", 06726 Mexico City, Mexico.

The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0. Read More

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Upregulation of pannexin-1 hemichannels explains the apparent death of the syncytiotrophoblast during human placental explant culture.

Placenta 2020 05 4;94:1-12. Epub 2020 Mar 4.

Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.

Background: It has been reported that during the culture of human placental explants, the syncytiotrophoblast dies between 3 and 24 h and is then replaced within 48 h by a new syncytiotrophoblast layer formed by the fusion of underlying cytotrophoblasts. Most frequently the death of the syncytiotrophoblast is indicated by the uptake of nuclear stains such as propidium iodide (PI). This process is reportedly similar in both early and late gestation placental explants. Read More

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Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-λ -sulfanenitrile Intermediate.

Angew Chem Int Ed Engl 2019 10 28;58(40):14303-14310. Epub 2019 Aug 28.

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, W12 0BZ, UK.

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. Read More

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October 2019

TLR4 deficiency has a protective effect in the MPTP/probenecid mouse model of Parkinson's disease.

Acta Pharmacol Sin 2019 Dec 6;40(12):1503-1512. Epub 2019 Aug 6.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Parkinson's disease (PD) is a multifactorial disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein. The etiology of PD is still not clear but systemic inflammation is proved to trigger and exacerbate DA neurons degeneration. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) and plays a major role in promoting the host immune. Read More

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December 2019

Gap junction mediated signaling between satellite glia and neurons in trigeminal ganglia.

Glia 2019 05 4;67(5):791-801. Epub 2019 Feb 4.

Laboratory of Experimental Surgery, Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Peripheral sensory ganglia contain the somata of neurons mediating mechanical, thermal, and painful sensations from somatic, visceral, and oro-facial organs. Each neuronal cell body is closely surrounded by satellite glial cells (SGCs) that have properties and functions similar to those of central astrocytes, including expression of gap junction proteins and functional dye coupling. As shown in other pain models, after systemic pain induction by intra-peritoneal injection of lipopolysaccharide, dye coupling among SGCs in intact trigeminal ganglion was enhanced. Read More

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The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers.

Pharmaceutics 2018 Sep 21;10(4). Epub 2018 Sep 21.

Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. Read More

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September 2018

Extracellular ATP Regulates CD73 and ABCC6 Expression in HepG2 Cells.

Front Mol Biosci 2018 14;5:75. Epub 2018 Aug 14.

Department of Sciences University of Basilicata, Potenza, Italy.

The ATP-binding cassette sub-family C member 6 transporter (ABCC6) is an ATP dependent transporter mainly found in the basolateral plasma membrane of hepatic and kidney cells. Mutations in gene were associated to the Pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by a progressive ectopic calcification of elastic fibers in dermal, ocular, and vascular tissues. It is reported that the over-expression of ABCC6 in HEK293 cells results in the cellular efflux of ATP and other nucleoside triphosphates, which in turn are rapidly converted into nucleoside monophosphates and pyrophosphate (PPi). Read More

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Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters .

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

Department of Pharmacology and PharmacoGenomics Research Center (PGRC), Inje University College of Medicine, Busan, Republic of Korea

The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using oocytes and stably transfected HEK-293 cells The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. Read More

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September 2018

Probenecid Disrupts a Novel Pannexin 1-Collapsin Response Mediator Protein 2 Interaction and Increases Microtubule Stability.

Front Cell Neurosci 2018 11;12:124. Epub 2018 May 11.

Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.

Neurite formation relies on finely-tuned control of the cytoskeleton. Here we identified a novel protein-protein interaction between the ion and metabolite channel protein Pannexin 1 (Panx1) and collapsin response mediator protein 2 (Crmp2), a positive regulator of microtubule polymerization and stabilization. Panx1 and Crmp2 co-precipitated from both Neuro-2a (N2a) cells and mouse ventricular zone (VZ) tissue. Read More

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Transporter-dependent cytotoxicity of antiviral drugs in primary cultures of human proximal tubular cells.

Toxicology 2018 07 5;404-405:10-24. Epub 2018 May 5.

Ardea Biosciences, San Diego, CA 92121 USA.

The role of plasma membrane transporters in the nephrotoxicity of two antiretroviral drugs, cidofovir and tenofovir, was studied in primary cultures of human proximal tubular (hPT) cells. Cells were grown on Transwell filter inserts to maintain epithelial polarity and access to either the apical or basolateral plasma membrane. The function of relevant membrane transporters, organic anion transporter 1 and 3 (OAT1/3), P-glycoprotein (multidrug resistance protein-1; P-gp or MDR1), and organic cation transporter 2 (OCT2), was validated by measurements of apical-to-basolateral and basolateral-to-apical fluxes of furosemide, digoxin, and metformin, respectively. Read More

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Functional Characterization of ABCC Proteins from and Their Involvement with Thiol Transport.

Front Microbiol 2018 14;9:205. Epub 2018 Feb 14.

Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Chagas disease is a neglected disease caused by the protozoan and affects 8 million people worldwide. The main chemotherapy is based on benznidazole. The efficacy in the treatment depends on factors such as the parasite strain, which may present different sensitivity to treatment. Read More

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February 2018

ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells.

PLoS One 2018 31;13(1):e0192180. Epub 2018 Jan 31.

Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.

ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines. Read More

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Mapping Extracellular pH of Gliomas in Presence of Superparamagnetic Nanoparticles: Towards Imaging the Distribution of Drug-Containing Nanoparticles and Their Curative Effect on the Tumor Microenvironment.

Contrast Media Mol Imaging 2017 22;2017:3849373. Epub 2017 Nov 22.

Magnetic Resonance Research Center, Yale University, New Haven, CT, USA.

Since brain's microvasculature is compromised in gliomas, intravenous injection of tumor-targeting nanoparticles containing drugs (D-NPs) and superparamagnetic iron oxide (SPIO-NPs) can deliver high payloads of drugs while allowing MRI to track drug distribution. However, therapeutic effect of D-NPs remains poorly investigated because superparamagnetic fields generated by SPIO-NPs perturb conventional MRI readouts. Because extracellular pH (pH) is a tumor hallmark, mapping pH is critical. Read More

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October 2018

OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam.

Int J Pharm 2018 Feb 23;537(1-2):172-182. Epub 2017 Dec 23.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address:

This study aimed to demonstrate that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between piperacillin and tazobactam. After co-administration with piperacillin in rats, the AUC of tazobactam in plasma was significantly increased, and t was prolonged with significant reduction in plasma clearance, renal clearance and cumulative urinary excretion. In rat and human kidney slices, probenecid, p-aminohippurate and benzylpenicillin inhibited the uptake of piperacillin and tazobactam. Read More

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February 2018

Ipratropium is 'luminally recycled' by an inter-play between apical uptake and efflux transporters in Calu-3 bronchial epithelial cell layers.

Int J Pharm 2017 Oct;532(1):328-336

Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, NG7 2RD, United Kingdom. Electronic address:

The mechanism by which quaternized anticholinergic bronchodilators permeate the airway epithelium remains controversial to date. In order to elucidate the role of drug transporters, ipratropium bidirectional transport as well as accumulation and release studies were performed in layers of the broncho-epithelial cell line Calu-3 grown at an air-liquid interface, in presence or absence of a range of transporter inhibitors. Unexpectedly, a higher transepithelial permeability was observed in the secretory direction, with an apparent efflux ratio of > 4. Read More

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October 2017

Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease.

Neurochem Int 2017 Nov 5;110:14-24. Epub 2017 Aug 5.

CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88400 Biberach an der Riss, Germany. Electronic address:

The modulation of the brain endocannabinoid system has been identified as an option to treat neurodegenerative diseases including Parkinson's disease (PD). Especially the elevation of endocannabinoid levels by inhibition of hydrolytic degradation represents a valuable approach. To evaluate whether monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) inhibition could be beneficial for PD, we examined in parallel the therapeutic potential of the highly selective MAGL inhibitor KML29 elevating 2-arachidonoylglyerol (2-AG) levels and the highly selective FAAH inhibitor PF-3845 elevating anandamide (AEA) levels in a chronic methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/probenecid) mouse model of PD. Read More

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November 2017

Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease.

Neurotox Res 2017 Oct 27;32(3):473-486. Epub 2017 Jun 27.

Department of Exercise Biochemistry, Korea National Sport University, Seoul, 138-763, Republic of Korea.

Accumulation of alpha-synuclein (α-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces α-Syn levels, the molecular mechanisms by which physical exercise decreases α-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases α-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD. Read More

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October 2017

Possible contribution of pannexin-1 to capsaicin-induced ATP release in rat nasal columnar epithelial cells.

Channels (Austin) 2017 Jul 10;11(4):273-280. Epub 2017 Feb 10.

a Department of Otorhinolaryngology-Head and Neck Surgery , University of Occupational and Environmental Health , Kitakyushu , Japan.

Current evidence indicates that transient receptor potential (TRP) channel activity involves a relationship between opening of pannexin-1 and release of ATP into the extracellular space. We examined the effects of agonists of thermosensitive TRP channels (TRPM8, TRPA1, TRPV1, and TRPV2) on ATP release from rat nasal mucosa, and measured ciliary beat frequency (CBF) using digital high-speed video imaging. Single-cell patch clamping from dissociated rat nasal columnar epithelial cells was performed to confirm the relationship between pannexin-1 and TRP. Read More

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Thyroxine (T) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides.

Front Neurol 2017 23;8:214. Epub 2017 May 23.

ER045, PRASE, Lebanese University, Beirut, Lebanon.

Thyroxine (T) enters the brain either directly across the blood-brain barrier (BBB) or indirectly the choroid plexus (CP), which forms the blood-cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with I-T and C-mannitol. Read More

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Prediction of renal transporter-mediated drug-drug interactions for a drug which is an OAT substrate and inhibitor using PBPK modelling.

Eur J Pharm Sci 2017 Aug 25;106:122-132. Epub 2017 May 25.

Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France.

A PBPK modelling approach was used to predict organic anion transporter (OAT) mediated drug-drug interactions involving S44121, a substrate and an inhibitor of OAT1 and OAT3. Model predictions were then compared to the results of a clinical DDI study which was carried out to investigate the interaction of S44121 with probenecid, tenofovir and ciprofloxacin. PBPK models were developed and qualified using existing clinical data, and inhibition constants were determined in vitro. Read More

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