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British Journal of Clinical Pharmacology Dec 2021Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets.... (Observational Study)
Observational Study
UNLABELLED
Oral flucloxacillin may be coadministered 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. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration).
RESULTS
Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid.
CONCLUSION
The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.
Topics: Adult; Anti-Bacterial Agents; Cross-Over Studies; Floxacillin; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Probenecid
PubMed: 33963595
DOI: 10.1111/bcp.14887 -
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 -
Xenobiotica; the Fate of Foreign... Apr 20171. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses...
1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.
Topics: Acetylcysteine; Animals; Biological Transport; Brain; Drug Interactions; Organic Anion Transporters; Plasma; Probenecid; Rats; Rats, Sprague-Dawley
PubMed: 27278858
DOI: 10.1080/00498254.2016.1187777 -
Journal of Neurotrauma Oct 2016Probenecid and N-acetylcysteine (NAC) can preserve intracellular levels of the vital antioxidant glutathione (GSH) via two distinct biochemical pathways. Probenecid...
Probenecid and N-acetylcysteine (NAC) can preserve intracellular levels of the vital antioxidant glutathione (GSH) via two distinct biochemical pathways. Probenecid inhibits transporter-mediated GSH efflux and NAC serves as a cysteine donor for GSH synthesis. We hypothesized that probenecid and NAC alone would maintain intracellular GSH concentrations and inhibit neuronal death after traumatic stretch injury, and that the drugs in combination would produce additive effects. Sex-segregated rat primary cortical neurons were treated with probenecid (100 μM) and NAC (50 μM), alone and in combination (Pro-NAC), then subjected to mechanical stretch (10s strain rate, 50% membrane deformation). At 24 h, both probenecid and NAC inhibited trauma-induced intracellular GSH depletion, lactate dehydrogenase (LDH) release, and propidium iodide (PI) uptake in both XY- and XX-neurons. Combined Pro-NAC treatment was superior to probenecid or NAC alone in maintenance of intracellular GSH and neuronal death assessed by PI uptake. Interestingly, caspase 3 activity 24 h after mechanical trauma was more prominent in XX-neurons, and treatment effects (probenecid, NAC, and Pro-NAC) were observed in XX- but not XY-neurons; however, XY-neurons were ultimately more vulnerable to mechanical stretch-induced injury than their XX counterparts, as was evidenced by more neuronal death detected by LDH release and PI uptake. In addition, after stretch injury in HT22 hippocampal cells, both NAC and probenecid were highly effective at reducing oxidative stress detected by dichlorofluorescein fluorescence. These in vitro data support further testing of this drug combination in models of traumatic neuronal injury in vivo.
Topics: Acetylcysteine; Animals; Brain Injuries, Traumatic; Cell Death; Cells, Cultured; Female; Glutathione; Male; Neurons; Neuroprotective Agents; Probenecid; Rats; Rats, Sprague-Dawley; Stress, Mechanical
PubMed: 26830358
DOI: 10.1089/neu.2015.4342 -
Lancet (London, England) Aug 1989The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment... (Clinical Trial)
Clinical Trial
The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment for human immunodeficiency virus infection. Zidovudine plasma concentrations were measured while subjects were receiving zidovudine alone, after 3 days of zidovudine plus 500 mg probenecid every 8 h, and after 3 days of zidovudine plus 500 mg probenecid plus 260 mg quinine sulphate every 8 h. A median increase of 80% in the area under the zidovudine plasma concentration/time curve occurred with the addition of probenecid. Quinine sulphate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal elimination of zidovudine. Probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs.
Topics: AIDS-Related Complex; Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Humans; Male; Middle Aged; Patient Compliance; Probenecid; Quinine; Zidovudine
PubMed: 2570186
DOI: 10.1016/s0140-6736(89)92087-4 -
Proceedings of the Royal Society of... Aug 1956
Topics: Gout; Probenecid
PubMed: 13359424
DOI: No ID Found -
British Medical Journal Jun 1979
Topics: Colchicine; Cortisone; Gout; Humans; Male; Probenecid; Sulfinpyrazone
PubMed: 466182
DOI: 10.1136/bmj.1.6179.1695 -
Pharmaceutical Research Nov 2020To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical...
PURPOSE
To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling.
METHODS
PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration-time curve (AUC) and peak plasma concentrations (C) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies.
RESULTS
The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI C ratios within 1.25-fold of the observed values, and all predicted DDI AUC and C ratios within 2.0-fold.
CONCLUSIONS
Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.
Topics: Administration, Intravenous; Administration, Oral; Adult; Biotransformation; Computer Simulation; Drug Elimination Routes; Drug Interactions; Female; Furosemide; Humans; Male; Models, Biological; Organic Anion Transporters; Probenecid; Rifampin
PubMed: 33237382
DOI: 10.1007/s11095-020-02964-z -
The Cochrane Database of Systematic... Feb 2018Gonorrhoea is a sexually transmitted infection that is caused by Neisseria gonorrhoeae, and is a major public health challenge today. N gonorrhoeae can be transmitted... (Review)
Review
BACKGROUND
Gonorrhoea is a sexually transmitted infection that is caused by Neisseria gonorrhoeae, and is a major public health challenge today. N gonorrhoeae can be transmitted from the mother's genital tract to the newborn during birth, and can cause gonococcal ophthalmia neonatorum as well as systemic neonatal infections. It can also cause endometritis and pelvic sepsis in the mother. This review updates and replaces an earlier Cochrane Review on antibiotics for treating this infectious condition.
OBJECTIVES
To assess the clinical effectiveness and harms of antibiotics for treating gonorrhoea in pregnant women.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2017), LILACS database (1982 to April 5, 2017), the WHO International Clinical Trials Registry Platform (ICTRP; April 5, 2017), ClinicalTrials.gov (April 5, 2017), the ISRCTN Registry (April 5, 2017), and Epistemonikos (April 5, 2017). We also searched reference lists of all retrieved articles.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing the use of antibiotics for treating gonorrhoea in pregnancy. The antibiotics could have been used alone or in combination, were administered parenterally, orally, or both, and were compared with another antibiotic.We included RCTs regardless of their publication status (published, unpublished, published as an article, an abstract, or a letter), language, or country. We applied no limits on the length of follow-up.We excluded RCTs using a cluster- or cross-over design, or quasi-RCTs.
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy.
MAIN RESULTS
We included two RCTs, that randomised 514 pregnant women (347 women analysed) at a mean gestational age of 22 weeks. Both trials were conducted in the outpatient department of the same two hospitals in the USA between 1993 and 2001, and had a follow-up of 14 days. One of the trials was sponsored by a drug company. We considered both trials to be at a high risk of bias.One trial compared ceftriaxone (125 mg, intramuscular) with cefixime (400 mg, oral); the other trial had three arms, and assessed ceftriaxone (250 mg, intramuscular) versus either amoxicillin (3 g, oral) plus probenecid (1 g, oral) or spectinomycin (2 g, intramuscular). We did not include the spectinomycin data because this medication is no longer produced. We were unable to conduct meta-analysis because the trials compared different medications.We found inconclusive evidence that there were clear differences in the cure of gonococcal infections (genital, extragenital, or both) between intramuscular ceftriaxone versus oral amoxicillin plus oral probenecid (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.98 to 1.16; one RCT; 168 women; very low-quality evidence) or intramuscular ceftriaxone versus oral cefixime (RR 0.99, 95% CI 0.91 to 1.08; one RCT; 95 women; very low-quality evidence).Neither of the trials reported on two of this review's primary maternal outcomes: incidence of obstetric complications (miscarriage, premature rupture of membranes, preterm delivery, or fetal death), or disseminated gonococcal infection, or on the incidence of neonatorum ophthalmia in the neonates.One trial reported one case of vomiting in the oral amoxacillin plus probenecid group. Trials reported pain at the injection sites, but did not quantify it. Hyperberbilurrubinemia was more frequent in neonates whose mothers were exposed to ceftriaxone. There were no clear differences between groups for neonatal malformation.
AUTHORS' CONCLUSIONS
This Cochrane Review found high levels of cure of gonococcal infections in pregnancy with the given antibiotic regimens. However, the evidence in this review is inconclusive as it does not support one particular regimen over another. This conclusion was based on very low-quality evidence (downgraded for poor trial design, imprecision) from two trials (involving 514 women), which we assessed to be at a high risk of bias for a number of domains. The harm profiles of the antibiotic regimes featured in this review remain unknown.High-quality RCTs are needed, with sufficient power to assess the clinical effectiveness and potential harms of antibiotics in pregnant women with gonorrhoea. These should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT),conducted following CONSORT recommendations, and based on Patient-Centered Outcomes Research Institute (PCORI) outcomes.
Topics: Amoxicillin; Anti-Bacterial Agents; Cefixime; Ceftriaxone; Female; Gonorrhea; Humans; Pregnancy; Pregnancy Complications, Infectious; Probenecid; Randomized Controlled Trials as Topic; Spectinomycin
PubMed: 29465747
DOI: 10.1002/14651858.CD011167.pub2 -
Critical Care Medicine Sep 2018To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.
DESIGN
Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).
SETTING
Thirty-six-bed PICU in a university-affiliated children's hospital.
PATIENTS AND SUBJECTS
Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.
INTERVENTION
Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.
MEASUREMENTS AND MAIN RESULTS
The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.
CONCLUSIONS
This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.
Topics: Acetylcysteine; Adjuvants, Pharmaceutic; Adolescent; Brain Injuries, Traumatic; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Humans; Injury Severity Score; Metabolomics; Probenecid
PubMed: 29742587
DOI: 10.1097/CCM.0000000000003203