RESUMEN
In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20-5.32) mg/L p < 0.001, 180 min 2.2 (1.58-3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88-1.42) mg/L p < 0.001, 180 min 0.5 (0.35-0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.
Asunto(s)
Antibacterianos , Estudios Cruzados , Penicilina V , Probenecid , Humanos , Probenecid/farmacocinética , Probenecid/farmacología , Probenecid/administración & dosificación , Masculino , Adulto , Femenino , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Penicilina V/farmacocinética , Penicilina V/administración & dosificación , Streptococcus pneumoniae/efectos de los fármacos , Adulto Joven , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Voluntarios Sanos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiologíaRESUMEN
BACKGROUND: Optimized antibiotic plasma predictor efficacy is essential in systemic infections. The uricosuric agent probenecid inhibits tubular excretion of antibiotics and may be used as ß-lactam pharmacokinetic enhancer (BLPKE), even though few data are currently available for this purpose. METHODS: We conducted a monocentric and retrospective observational study including all patients who received probenecid in combination with parenteral ß-lactam antibiotics for systemic infections from Jan 1, 2014 to Dec 31, 2019. Demographics, infection characteristics, treatment and ATC (antibiotics trough concentration) were investigated. RESULTS: All in all, 38 patients were included. Eight patients had a history of sickle cell disease. Hyperfiltration (defined as eGFR>130mL/min/1.73m2) was detected in twenty-one patients including six with sickle cell disease. Probenecid (500mg q6h orally) was added to antibiotics for a median (IQR) of 13 days (6.75-21.75), after a median (IQR) time lapse of 7 days (4-16) following the initiation of antibiotics. Probenecid was administered for low antibiotic trough concentration in 29 patients, for increased renal clearance in 5 patients and for persisting fever despite antibiotic therapy in 4 patients (including 1 infective relapse). A second plasma trough concentration, following probenecid administration, was available in 19 patients within a median (IQR) 3 days (2-5). Probenecid induced increased ATC in 18/19 patients (94.7%), with a median (IQR) change of +228.4% (IQR 38.7-633). No major adverse effects were reported. CONCLUSION: Probenecid could be a BLPKE. Our data suggest this drug should be used more often to optimize ß-lactam pharmacokinetics in clinical practice.
Asunto(s)
Anemia de Células Falciformes , Probenecid , Antibacterianos/uso terapéutico , Humanos , Probenecid/farmacocinética , Probenecid/uso terapéutico , Estudios Retrospectivos , beta-Lactamas/uso terapéuticoRESUMEN
As an expansion investigation of drug-drug interaction (DDI) from previous clinical trials, additional plasma endogenous metabolites were quantitated in the same subjects to further identify the potential biomarkers of organic anion transporter (OAT) 1/3 inhibition. In the single dose, open label, three-phase with fixed order of treatments study, 14 healthy human volunteers orally received 1000 mg probenecid alone, or 40 mg furosemide alone, or 40 mg furosemide at 1 hour after receiving 1000 mg probenecid on days 1, 8, and 15, respectively. Endogenous metabolites including kynurenic acid, xanthurenic acid, indo-3-acetic acid, pantothenic acid, p-cresol sulfate, and bile acids in the plasma were measured by liquid chromatography-tandem mass spectrometry. The Cmax of kynurenic acids was significantly increased about 3.3- and 3.7-fold over the baseline values at predose followed by the treatment of probenecid alone or in combination with furosemide respectively. In comparison with the furosemide-alone group, the Cmax and area under the plasma concentration-time curve (AUC) up to 12 hours of kynurenic acid were significantly increased about 2.4- and 2.5-fold by probenecid alone, and 2.7- and 2.9-fold by probenecid plus furosemide, respectively. The increases in Cmax and AUC of plasma kynurenic acid by probenecid are comparable to the increases of furosemide Cmax and AUC reported previously. Additionally, the plasma concentrations of xanthurenic acid, indo-3-acetic acid, pantothenic acid, and p-cresol sulfate, but not bile acids, were also significantly elevated by probenecid treatments. The magnitude of effect size analysis for known potential endogenous biomarkers demonstrated that kynurenic acid in the plasma offers promise as a superior addition for early DDI assessment involving OAT1/3 inhibition. SIGNIFICANCE STATEMENT: This article reports that probenecid, an organic anion transporter (OAT) 1 and OAT3 inhibitor, significantly increased the plasma concentrations of kynurenic acid and several uremic acids in human subjects. Of those, the increases of plasma kynurenic acid exposure are comparable to the increases of furosemide by OAT1/3 inhibition. Effect size analysis for known potential endogenous biomarkers revealed that plasma kynurenic acid is a superior addition for early drug-drug interaction assessment involving OAT1/3 inhibition.
Asunto(s)
Biomarcadores Farmacológicos , Interacciones Farmacológicas/fisiología , Furosemida/farmacología , Ácido Quinurénico , Proteína 1 de Transporte de Anión Orgánico , Transportadores de Anión Orgánico Sodio-Independiente , Probenecid/farmacocinética , Adyuvantes Farmacéuticos/farmacocinética , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Cromatografía Liquida/métodos , Furosemida/farmacocinética , Voluntarios Sanos , Humanos , Ácido Quinurénico/análisis , Ácido Quinurénico/sangre , Proteína 1 de Transporte de Anión Orgánico/antagonistas & inhibidores , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Espectrometría de Masas en Tándem/métodosRESUMEN
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. Simultaneous fitting of biomarker plasma and urine data in the presence and absence of potent OAT1/3 inhibitor (probenecid, 500 mg every 6 h) was performed. The impact of study design (multiple vs. single dose of OAT1/3 inhibitor) and ability to detect interactions in the presence of weak/moderate OAT1/3 inhibitors was investigated, together with corresponding power calculations. The population models developed successfully described biomarker baseline and PDA/HVA OAT1/3-mediated interaction data. No prominent effect of circadian rhythm on PDA and HVA individual baseline levels was evident. Renal elimination contributed greater than 80% to total clearance of both endogenous biomarkers investigated. Estimated probenecid unbound in vivo OAT inhibitory constant was up to 6.4-fold lower than in vitro values obtained with PDA as a probe. The PDA model was successfully verified against independent literature reported datasets. No significant difference in power of DDI detection was found between multiple and single dose study design when using the same total daily dose of 2000 mg probenecid. Model-based simulations and power calculations confirmed sensitivity and robustness of plasma PDA data to identify weak, moderate, and strong OAT1/3 inhibitors in an adequately powered clinical study to support optimal design of prospective clinical OAT1/3 interaction studies.
Asunto(s)
Simulación por Computador , Interacciones Farmacológicas , Ácido Homovanílico/farmacocinética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Probenecid/farmacocinética , Ácido Piridóxico/farmacocinética , Biomarcadores/metabolismo , Estudios Cruzados , Femenino , Voluntarios Sanos , Ácido Homovanílico/sangre , Humanos , Masculino , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Probenecid/sangre , Ácido Piridóxico/sangreRESUMEN
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 (Cmax) 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 Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax 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.
Asunto(s)
Furosemida/farmacocinética , Modelos Biológicos , Transportadores de Anión Orgánico/antagonistas & inhibidores , Probenecid/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Biotransformación , Simulación por Computador , Vías de Eliminación de Fármacos , Interacciones Farmacológicas , Femenino , Furosemida/administración & dosificación , Furosemida/sangre , Humanos , Masculino , Transportadores de Anión Orgánico/metabolismo , Probenecid/administración & dosificación , Probenecid/sangre , Rifampin/farmacocinéticaRESUMEN
BACKGROUND AND OBJECTIVE: A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics. METHODS: In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure. RESULTS: The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC0-tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0-tz by 172% and Cmax by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC0-tz unaltered, Cmax + 22%). CONCLUSIONS: Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development. CLINICAL TRIAL REGISTRATION: EudraCT number 2017-001549-29.
Asunto(s)
Cimetidina , Probenecid , Rifampin , Verapamilo , Área Bajo la Curva , Cimetidina/farmacocinética , Interacciones Farmacológicas , Humanos , Masculino , Probenecid/farmacocinética , Rifampin/farmacocinética , Verapamilo/farmacocinéticaRESUMEN
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. METHODS: We cultured first trimester placental explants for up to 48 h and tested membrane intactness by exposure to PI. Connexin and pannexin mRNAs were quantified by RT-PCR and protein levels determined by immunofluorescence. The syncytiotrophoblast membrane leak was determined by culturing explants in the presence of hemichannel blockers. Extrusion of extracellular vesicles from the syncytiotrophoblast was quantified. RESULTS: Nuclei of the syncytiotrophoblast were stained with PI following approximately 4 h of culture and this was prevented by culturing the explants with pannexin-1 blockers. Expression of pannexin-1 hemichannels increased during explant culture (p = 0.0027). Extracellular vesicles were most abundantly extruded from the explants during the first 3 h of culture and the temporal pattern of extrusion was unaltered by blocking hemichannels. DISCUSSION: We show the mechanism of uptake of nuclear non-viability stains into the syncytiotrophoblast during explant culture is via upregulation of pannexin 1 hemichannels. Contrary to suggestions by some, the production of extracellular vesicles from cultured placental explants is not an in vitro artefact resulting from the apparent death of the syncytiotrophoblast in explant cultures.
Asunto(s)
Muerte Celular/fisiología , Conexinas/genética , Proteínas del Tejido Nervioso/genética , Placenta/fisiología , Técnicas de Cultivo de Tejidos , Trofoblastos/fisiología , Conexina 43/antagonistas & inhibidores , Conexina 43/genética , Conexina 43/fisiología , Conexinas/antagonistas & inhibidores , Conexinas/fisiología , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/fisiología , Embarazo , Probenecid/farmacocinética , Propidio/metabolismo , ARN Mensajero/análisis , Factores de Tiempo , Trofoblastos/química , Regulación hacia ArribaRESUMEN
Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150â¯mg/kg) hepatotoxicity was exacerbated by probenecid (100â¯mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%-58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Catárticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Emodina/toxicidad , Glucuronosiltransferasa/antagonistas & inhibidores , Probenecid/toxicidad , Fármacos Renales/toxicidad , Animales , Catárticos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Sinergismo Farmacológico , Emodina/farmacocinética , Células Hep G2 , Humanos , Cinética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Probenecid/farmacocinética , Ratas , Ratas Sprague-Dawley , Fármacos Renales/farmacocinéticaRESUMEN
AIMS: The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure. METHODS: This phase 1, open-label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5-day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4. RESULTS: Coadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of probenecid were 128.7% (121.9-135.7%) and 176.1% (171.9-180.3%), respectively. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of cimetidine were 117.1% (111.0-123.6%) and 143.7% (140.3-147.2%), respectively. Mean (standard deviation) renal clearance of mirogabalin (l h-1 ) was substantially slower after probenecid [6.67 (1.53)] or cimetidine [7.17 (1.68)] coadministration, compared with mirogabalin alone [11.3 (2.39)]. Coadministration of probenecid or cimetidine decreased mirogabalin mean (standard deviation) apparent total body clearance [10.5 (2.33) and 12.8 (2.67) l h-1 , respectively, vs. 18.4 (3.93) for mirogabalin alone]. CONCLUSIONS: A greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs. a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2-fold), no a priori dose adjustment is recommended.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacocinética , Cimetidina/farmacocinética , Tasa de Depuración Metabólica/efectos de los fármacos , Probenecid/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Compuestos Bicíclicos con Puentes/administración & dosificación , Cimetidina/administración & dosificación , Estudios Cruzados , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada/métodos , Femenino , Voluntarios Sanos , Herpes Zóster/complicaciones , Herpes Zóster/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Probenecid/administración & dosificación , Eliminación Renal/efectos de los fármacosRESUMEN
AIM: No antiviral medications are currently approved to treat enterovirus (EV)-associated disease or prevent EV infection. METHODS: In this study, a series of probenecid derivatives were designed via a rational strategy and synthesized to obtain more potent anti-EV agents. RESULTS: Compounds 8 and 24 exhibited the most potent activity against EV D68 and A71, with half maximal effective concentration (EC50) values of 2.49/2.09 and 2.59/2.41 µM, respectively, and revealed a broad inhibition spectrum toward other EV strains, with high selectivity indices. Additionally, compounds 8 and 24 showed good stability in rat serum, with half-lives of 48.39 and 60.26 min, respectively. CONCLUSION: Compounds 8 and 24 are the promising candidates for the development of new agents against EV D68 and A71 viruses.
Asunto(s)
Antivirales/síntesis química , Diseño de Fármacos , Enterovirus/efectos de los fármacos , Probenecid/síntesis química , Animales , Antivirales/farmacocinética , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Infecciones por Enterovirus , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Probenecid/análogos & derivados , Probenecid/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
BACKGROUND: There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. METHODS: IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. RESULTS: There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 µg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. CONCLUSIONS: Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322009.
Asunto(s)
Acetilcisteína/farmacocinética , Adyuvantes Farmacéuticos/farmacocinética , Antioxidantes/farmacocinética , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Probenecid/farmacocinética , Acetilcisteína/sangre , Acetilcisteína/líquido cefalorraquídeo , Acetilcisteína/farmacología , Adyuvantes Farmacéuticos/farmacología , Adolescente , Antioxidantes/farmacología , Biomarcadores/sangre , Temperatura Corporal , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/líquido cefalorraquídeo , Lesiones Traumáticas del Encéfalo/mortalidad , Niño , Preescolar , Método Doble Ciego , Esquema de Medicación , Femenino , Escala de Coma de Glasgow , Escala de Consecuencias de Glasgow , Humanos , Presión Intracraneal/efectos de los fármacos , Intubación Gastrointestinal , Masculino , Probenecid/sangre , Probenecid/líquido cefalorraquídeo , Probenecid/farmacología , Análisis de SupervivenciaRESUMEN
We demonstrate, by means of on-tissue mass spectrometry of tissue sections, that the drug probenecid can penetrate the blood-brain barrier. This method holds general promise for the detection and distribution of small molecule drugs within organ and tissue compartments.
Asunto(s)
Adyuvantes Farmacéuticos/farmacocinética , Barrera Hematoencefálica/metabolismo , Espectrometría de Masas/métodos , Probenecid/farmacocinética , Adyuvantes Farmacéuticos/farmacología , Animales , Ratones , Especificidad de Órganos/efectos de los fármacos , Probenecid/farmacologíaRESUMEN
BACKGROUND: Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The goal of these studies was to investigate potential drug-drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). METHODS: Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. RESULTS: In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-∞: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-∞: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated. CONCLUSIONS: Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100.
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Gemfibrozilo/farmacocinética , Glucósidos/farmacocinética , Probenecid/farmacocinética , Rifampin/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Adolescente , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Probenecid (PROB) has been widely used for long time for different clinical purposes, from gout treatment to designs as a coadjutant for antibiotic agents. Among its many properties, the ability of PROB to preserve high concentrations of several metabolites and other agents in the CNS, together with its relative lack of side-effects, have made this drug a valuable pharmacological tool for clinical and basic research. Nowadays, biomedical research offers evidence about new targets for PROB that may help to explain its many beneficial actions. In this regard, despite most of its protective actions in the brain have been largely related to its capacity to accumulate the inhibitory metabolite kynurenic acid to further inhibit the glutamate-related excitotoxicity in different animal models of neurological disorders, in this review we describe the basic aspects of PROB's pharmacokinetics and mechanisms of action and discuss other alternative targets recently described for this drug that may complement its pattern of activity in the CNS, including its role as anti-inflammatory and anti-nociceptive agent when targeting different key proteins.
Asunto(s)
Encéfalo/efectos de los fármacos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Probenecid/uso terapéutico , Animales , Interacciones Farmacológicas , Humanos , Quinurenina/metabolismo , Modelos Neurológicos , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/farmacología , Probenecid/efectos adversos , Probenecid/farmacocinética , Probenecid/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients. METHODS: We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. RESULTS: The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 µg/mL, were significantly below the 36 µg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05). CONCLUSIONS: Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.
Asunto(s)
Antivirales/farmacocinética , Virus BK/efectos de los fármacos , Citosina/análogos & derivados , Enfermedades Renales/metabolismo , Trasplante de Riñón , Organofosfonatos/farmacocinética , Infecciones por Polyomavirus/metabolismo , Infecciones Tumorales por Virus/metabolismo , Adyuvantes Farmacéuticos/farmacocinética , Adulto , Anciano , Área Bajo la Curva , Cidofovir , Estudios Cruzados , Citosina/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular , Semivida , Humanos , Enfermedades Renales/virología , Masculino , Persona de Mediana Edad , Probenecid/farmacocinética , Viremia/metabolismoRESUMEN
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
Asunto(s)
Antimaláricos/administración & dosificación , Quimioprevención/métodos , Malaria Falciparum/prevención & control , Complicaciones Infecciosas del Embarazo/prevención & control , Probenecid/administración & dosificación , Pirimetamina/administración & dosificación , Sulfadoxina/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Quimioprevención/efectos adversos , Combinación de Medicamentos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Humanos , Malaria Falciparum/tratamiento farmacológico , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Probenecid/efectos adversos , Probenecid/farmacocinética , Pirimetamina/efectos adversos , Pirimetamina/farmacocinética , Sulfadoxina/efectos adversos , Sulfadoxina/farmacocinética , Resultado del TratamientoRESUMEN
Probenecid was initially developed with the goal of reducing the renal excretion of antibiotics, specifically penicillin. It is still used for its uricosuric properties in the treatment in gout, but its clinical relevance has sharply fallen and is rarely used today for either. Interestingly, throughout the last 60 years, there have been a host of apparently unrelated studies using probenecid in the clinical and basic research arena, including its potential use in the diagnosis and treatment of depression and its use to prevent fura-2 leakage in calcium transient studies. Recently, it has been shown that it is also an agonist of the Transient Receptor Potential Vanilloid 2 channel. Due to its unique action and new findings implicating TRPV channels in physiology and in disease, probenecid may have a new future as a research tool, and perhaps as a clinical agent in the neurology and cardiology fields. We review the history of probenecid in this paper and its potential future uses.
Asunto(s)
Probenecid/farmacocinética , Probenecid/uso terapéutico , Uricosúricos/farmacocinética , Uricosúricos/uso terapéutico , Animales , Antibacterianos/antagonistas & inhibidores , Antibacterianos/farmacocinética , Depresión/tratamiento farmacológico , Depresión/metabolismo , Fura-2/metabolismo , Gota/tratamiento farmacológico , Gota/metabolismo , Humanos , Probenecid/química , Canales Catiónicos TRPV/fisiología , Uricosúricos/químicaRESUMEN
The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([(14)C]M-III). The elimination half-life of (14)C in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [(14)C]M-III at 0.5 mg/kg to rats and dogs. The in vitro and in vivo plasma protein binding ratios of M-III were relatively high and were the same in both species. The intrinsic clearance (CL(int)) of M-III in rats was much higher than the glomerular filtration rate in rats. Furthermore, the concentration of [(14)C]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [(14)C]M-III in the kidney was very much lower than that in the plasma. These results indicated that M-III was effectively taken up into the kidney and was excreted into the urine in rats; however, in dogs, ineffective renal uptake of M-III was presumed. When [(14)C]M-III and probenecid were simultaneously and continually infused intravenously to rats, the CL(int) of M-III decreased with increasing plasma concentrations of probenecid, indicating that kidney uptake of M-III in rats was inhibited by probenecid. It was also thought that uptake by the organic anion transport system(s) in the basolateral membrane is involved in the renal uptake of M-III in rats. The pharmacokinetic differences of M-III between rats and dogs are considered to be mainly caused by the difference in the urinary excretion via the renal distribution processes.
Asunto(s)
Compuestos de Anilina/farmacocinética , Bencenosulfonatos/farmacocinética , Sulfonamidas/metabolismo , Compuestos de Anilina/sangre , Compuestos de Anilina/orina , Animales , Bencenosulfonatos/sangre , Bencenosulfonatos/orina , Unión Competitiva , Proteínas Sanguíneas/metabolismo , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Perros , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Inyecciones Intravenosas , Riñón/metabolismo , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica , Probenecid/sangre , Probenecid/farmacocinética , Unión Proteica , Ratas Endogámicas , Especificidad de la Especie , Distribución TisularRESUMEN
OBJECTIVE: To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and oxypurinol (the active metabolite of allopurinol) in patients with gout. METHODS: This was an open-label observational clinical study. Blood and urine samples were collected to measure oxypurinol and urate concentrations. We examined the effects of adding probenecid to allopurinol therapy upon plasma concentrations and renal clearances of urate and oxypurinol. RESULTS: Twenty patients taking allopurinol 100-400 mg daily completed the study. Maximum coadministered doses of probenecid were 250 mg/day (n = 1), 500 mg/day (n = 19), 1000 mg/day (n = 7), 1500 mg/day (n = 3), and 2000 mg/day (n = 1). All doses except the 250 mg daily dose were divided and dosing was twice daily. Estimated creatinine clearances ranged from 28 to 113 ml/min. Addition of probenecid 500 mg/day to allopurinol therapy decreased plasma urate concentrations by 25%, from mean 0.37 mmol/l (95% CI 0.33-0.41) to mean 0.28 mmol/l (95% CI 0.24-0.32) (p < 0.001); and increased renal urate clearance by 62%, from mean 6.0 ml/min (95% CI 4.5-7.5) to mean 9.6 ml/min (95% CI 6.9-12.3) (p < 0.001). Average steady-state plasma oxypurinol concentrations decreased by 26%, from mean 11.1 mg/l (95% CI 5.0-17.3) to mean 8.2 mg/l (95% CI 4.0-12.4) (p < 0.001); and renal oxypurinol clearance increased by 24%, from mean 12.7 ml/min (95% CI 9.6-15.8) to mean 16.1 ml/min (95% CI 12.0-20.2) (p < 0.05). The additional hypouricemic effect of probenecid 500 mg/day appeared to be lower in patients with renal impairment. CONCLUSION: Coadministration of allopurinol with probenecid had a significantly greater hypouricemic effect than allopurinol alone despite an associated reduction of plasma oxypurinol concentrations. Australian Clinical Trials Registry ACTRN012606000276550.
Asunto(s)
Alopurinol/farmacología , Alopurinol/farmacocinética , Gota/tratamiento farmacológico , Probenecid/farmacología , Probenecid/farmacocinética , Alopurinol/administración & dosificación , Interacciones Farmacológicas , Quimioterapia Combinada , Gota/metabolismo , Supresores de la Gota/farmacocinética , Supresores de la Gota/farmacología , Humanos , Masculino , Persona de Mediana Edad , Oxipurinol/sangre , Oxipurinol/orina , Probenecid/administración & dosificación , Estudios Prospectivos , Ácido Úrico/sangre , Ácido Úrico/orina , Uricosúricos/farmacocinética , Uricosúricos/farmacologíaRESUMEN
Nephrotoxicity is a common and often clinically relevant adverse drug reaction. Mechanisms include vascular, tubulo-toxic, tubulo-obstructive, and immunological effects. Drug-drug interactions may occur at a pharmacokinetic or pharmacodynamic level. Such interactions can both increase (cisplatin and aminoglycoside) but also protect from nephrotoxicity (cidofovir and probenecid).Important measures for preventing nephrotoxicity are (1) consideration of potential pharmacokinetic and pharmacodynamic interactions when prescribing a drug, (2) prescription of nephrotoxic drugs for the shortest possible period, (3) detection of high-risk patients, and (4) consideration of hydration and prophylactic comedication.