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PubMed2004

Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats.

Overexpression of multidrug efflux transporters such as P-glycoprotein (Pgp; ABCB1) or multidrug resistance proteins (MRPs; ABCC) in the blood-brain barrier has recently been suggested to explain, at least in part, pharmacoresistance in epilepsy, which affects about 30% of all patients with this common brain disorder. The novel antiepileptic drug (AED) levetiracetam (LEV) is an effective and well tolerated drug in many patients with otherwise AED-refractory epilepsy. One explanation for the favorable efficacy of LEV in pharmacoresistant patients would be that LEV is not a substrate for Pgp or MRPs in the BBB. In the present study, we used in vivo microdialysis in rats to study whether the concentration of LEV in the extracellular fluid of the cerebral cortex can be modulated by inhibition of Pgp or MRPs, using the Pgp inhibitor verapamil and the MRP1/2 inhibitor probenecid. Local perfusion with verapamil or probenecid via the microdialysis probe did not increase the extracellular brain concentration of LEV, which is in contrast to various other AEDs which have been studied previously by the same experimental protocol in this model. The data indicate that brain uptake of LEV is not affected by Pgp or MRP1/2 which may be an important reason for its antiepileptic efficacy in patients whose seizures are poorly controlled by other AEDs.

ATP-Binding Cassette Transporters↗
PubMed2006

DNA damage caused by benzo(a)pyrene in MCF-7 cells is increased by verapamil, probenecid and PSC833.

The aim of this study was to clarify whether pharmaceutical drugs capable of inhibiting ABC-transporters affect the toxicity of benzo(a)pyrene (BP). MCF-7 breast adenocarcinoma cells were cultured for 24 and 48 h with benzo(a)pyrene (1 microM) and the transporter inhibitors verapamil (0.125-100 microM), PSC833 (0.05-5 microM) or probenecid (0.05-2 mM). DNA binding of benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) was analyzed by synchronous fluorescence spectrophotometry and p53 protein by immunoblotting. BP metabolism was studied using thin layer chromatography (TLC). MTT assay and ATP quantitation were used for the analysis of cell viability. At 24 h there was no statistically significant increase in the DNA-adduct formation by any of the used inhibitors. However, at 48 h all of the inhibitors, in concentrations known to effectively block ABC transporters, increased the BPDE-DNA adduct formation 1.5 to 2-fold compared to adduct formation with BP only. PSC833 and verapamil also increased p53 protein expression at 48 h (p<0.05). Probenecid decreased glucuronidation of (3)H-BP metabolites. Other inhibitors did not decrease statistically significantly the overall formation of water-soluble metabolites. BP alone slightly decreased viability of cells at 48 h according to ATP quantitation as compared to vehicle treated controls (86.4+/-16.4%). Even though the used inhibitors showed some cytotoxicity, the combination of BP and inhibitors did not decrease cell viability in synergistic manner. According to these results certain pharmaceutical drugs may increase DNA damage caused by benzo(a)pyrene in MCF-7 cells at least partly through the inhibition of transporters. Taking into account the complex metabolism of BP and lack of specificity of the inhibitors used, it is likely that increased DNA damage seen in this study was the result of multiple interactions between the inhibitors, BP metabolism and the efflux of the compounds.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1975

Probenecid and rifampicin serum levels.

Serum-levels of rifampicin were investigated in patients receiving rifampicin alone or with other antituberculosis drugs. 2 g of probenecid given 30 min before 300 mg of rifampicin did not result in raising serum levels to more than half those achieved with the standard 600 mg dose of rifampicin. Hence probenecid should not be used to reduce rifampicin dosage in antituberculosis therapy.

Administration, Oral↗
PubMed1981

The simultaneous analysis of clofibric acid and probenecid and the direct analysis of clofibric acid glucuronide by high-performance liquid chromatography.

A rapid and selective high-performance liquid chromatographic method for the simultaneous quantitative analysis of clofibric acid and probenecid in plasma and urine and for the direct analysis of clofibric acid glucuronide in plasma is described. Both methods involve direct injection of deproteinised body fluids. Concentrations of as low as 10 mg/l of clofibric acid and probenecid and 1.5 mg/l of clofibric acid glucuronide can be measured by the analysis. The coefficient of variance for these methods ranges from 1--7%.

Chromatography, High Pressure Liquid↗
PubMed1986

Determination of benzylpenicillin and probenecid in human body fluids by high-performance liquid chromatography.

A method for the determination of benzylpenicillin and probenecid concentrations in human body fluids using ion-pair reversed-phase chromatography with UV detection has been developed. For plasma samples two extraction techniques were investigated. Precipitation of the plasma proteins with acetonitrile followed by liquid-liquid extraction offered the best results. The limits of detection were 0.5 microgram/ml for benzylpenicillin and 0.25 microgram/ml for probenecid, which offer sufficient sensitivity for application in pharmacokinetic experiments.

Body Fluids↗
PubMed1994

Column-switching techniques for screening of diuretics and probenecid in urine samples.

A method based on high-performance liquid chromatography using column-switching is described for the screening of diuretics and probenecid in urine samples. The system uses a 20- x 2.1-mm i.d. precolumn, packed with a Hypersil ODS-C18, 30-microns stationary phase, for the on-line sample cleanup and enrichment. Untreated urine samples are directly injected, and the precolumn is flushed for 1 min with water to eliminate polar matrix components. The retained analytes are then back-flushed by means of a six-port switching valve onto a Hypersil ODS-C18 analytical column (5 microns, 250- x 4-mm i.d.), where they are separated using an acetonitrile/phosphate buffer (pH = 3) gradient elution. Under these conditions, the separation and identification of diuretics and probenecid can be achieved with satisfactory selectivity and sensitivity. The described procedure is very simple and rapid since no off-line manipulation of the sample is required, the total analysis time being ca. 15 min.

Chromatography, High Pressure Liquid↗
PubMed2002

Rapid internal acyl migration and protein binding of synthetic probenecid glucuronides.

Internal acyl migration reactions of drug 1-O-acyl-beta-D-glucopyranuronates (1beta-acyl glucuronides) are of interest because of their possible role in covalent binding to proteins and consequent adverse effects. The reactivity of the synthetic probenecid 1beta-acyl glucuronide (PRG), the principal metabolite of probenecid (PR) in humans, has been investigated in terms of acyl migration, hydrolysis, and covalent binding to proteins in phosphate buffer (pH 7.4) and human plasma at 37 degrees C. PRG primarily degraded by acyl migration according to apparent first-order kinetics and the 2-, 3-, and 4-acyl isomers sequentially appeared as both alpha- and beta-anomeric forms. In addition, small amounts of PRG and extremely labile 1alpha-acyl isomer existed in the equilibrated mixture favoring the 2alpha/beta-acyl isomer, that provided significant information regarding the mechanism of acyl migration. All of the positional isomers and anomers were characterized using preparative HPLC and NMR spectroscopy. Acyl migration was observed to predominate over hydrolysis in both media although the extent of hydrolysis in plasma was larger than that in the buffer. The overall degradation half-lives (h) in the buffer and plasma were 0.27 +/- 0.003 and 0.17 +/- 0.007, respectively. The covalent binding rapidly proceeded mainly via the Schiff's base mechanism and reached a plateau after 2 h of incubation. The maximal binding was 146 +/- 4.8 pmol/mg of protein, and ca. 10% of the initial concentration of PRG. These results indicated that PRG is most labile and susceptible to acyl migration of all the drug acyl glucuronides reported to date in the physiological conditions, and highly reactive to plasma proteins, that could provide a possible explanation for the immunologically based adverse effects of PR.

Acylation↗
PubMed2004

Renal secretion of the antiviral nucleoside analog AM188 is inhibited by probenecid, p-aminohippuric acid, and cimetidine in the isolated perfused rat kidney.

PURPOSE: To investigate the effects of potential inhibitors of membrane transport on the tubular secretion of AM188, an antiviral guanosine analog, in the isolated perfused rat kidney (IPK). METHODS: AM188 was administered to the IPK perfusate as a bolus/infusion regimen. In inhibitor groups, probenecid, p-aminohippuric acid (PAH), cimetidine, or nitrobenzylthioinosine was added to the perfusing medium. RESULTS: In control IPKs, the ratio of renal clearance of AM188 (CLR) to GFR was 7.7 +/- 0.51 (mean +/- SD). The CL(R)/GFR ratio for AM188 was 6.20 +/- 0.41*, 2.85 +/- 0.20*, 1.45 +/- 0.07*, and 0.80 +/- 0.01* when the concentration of probenecid in perfusate was 10, 50, 100, and 1000 microM, respectively (*p < 0.05 compared to control group); the ratio was 7.71 +/- 0.38, 6.02 +/- 0.42*, 1.71 +/- 0.15*, and 0.91 +/- 0.07* for the PAH group and 6.42 +/- 1.70*, 5.33 +/- 1.53*, 3.16 +/- 0.81*, and 1.21 +/- 0.20* for the cimetidine group when the concentrations were 10, 100, 1000 and 10,000 microM, respectively; and the ratio was 5.33 +/- 0.21* when the concentration of nitrobenzylthioinosine was 5 microM. CONCLUSIONS: These results suggest that renal tubular secretion of AM188 involves organic anion and cation transport systems.

Animals↗
PubMed1988

The influence of nonsteroidal anti-inflammatory drugs and probenecid on the renal response to and kinetics of piretanide in man.

The mechanism by which nonsteroidal antiinflammatory drugs interfere with the action of loop diuretics is not clear. We studied the renal response to an acute challenge of piretanide superimposed on pretreatment with either placebo, probenecid, indomethacin, or piroxicam in seven maximally hydrated subjects. No change was seen in glomerular filtration rate, as measured by creatinine clearance, throughout the experiments. When compared with responses to piretanide challenge after placebo pretreatment, probenecid reduced by 65% the peak fractional excretion of sodium (FENa), with a corresponding reduction in diuretic excretion. Pretreatment with indomethacin reduced peak FENa by 35%, but urinary delivery of piretanide was not altered. In contrast, piroxicam did not influence FENa but significantly reduced the delivery of both sodium and piretanide into urine. We conclude that the activity of nonsteroidal antiinflammatory drugs within the renal tubule varies among individual drugs and cannot be explained solely by their common mechanism of antiinflammatory action.

Administration, Oral↗
PubMed2003

Interaction of ibuprofen and probenecid with drug metabolizing enzyme phenotyping procedures using caffeine as the probe drug.

AIMS: To examine the suspected inhibitory potential of the over-the-counter (OTC) drug ibuprofen on N-acetyltransferase 2 (NAT2) in vitro and in vivo and the possible implications for phenotyping procedures using caffeine as probe drug. METHODS: We first studied the inhibitory effect of ibuprofen on NAT2 in vitro, using human liver cytosol and sulfamethazine as substrate. In vivo 15 fast and 15 slow acetylating healthy volunteers were treated with a single dose of ibuprofen (800 mg) orally and phenotyped for NAT2, CYP1A2, and xanthine oxidase (XO) with caffeine as probe drug before and during drug treatment. Because of unexpected in vivo results with ibuprofen this study was repeated in 20 healthy volunteers with probenecid, a model substrate of renal organic anion transport (OAT). For phenotyping tests a urine sample was collected 6 h after caffeine (200 mg) intake. The caffeine metabolites acetyl-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) were quantified by HPLC, and the corresponding metabolic ratios for CYP1A2, NAT2, and XO were then calculated. Genotyping for NAT2 was performed with standard PCR-RFLP methods. RESULTS: In vitro, with human liver cytosol an inhibition by ibuprofen of the acetylation of sulfamethazine with Ki values between 2.2 and 3.1 mm was observed. Surprisingly, in vivo a significant (P < 0.001) increase of the acetyl-6-formylamino-3-methyluracil/1-methylxanthine (AFMU/1MX) urinary ratio from 0.97 +/- 0.16 to 1.08 +/- 0.18 (95% CI on the difference 0.049, 0.170) was found, indicating an apparent elevation of NAT2 activity. In contrast, no change was observed for the ratios used for XO and CYP1A2. Because an induction of NAT2 could be excluded, an interaction of ibuprofen with the tubular secretion of some of the caffeine metabolites was assumed. To prove this assumption, the in vivo study was repeated with probenecid, a model substrate of the renal OAT system. Again, a prominent elevation of the AFMU/1MX ratio from 0.97 +/- 0.21 to 1.53 +/- 0.35 was found (P < 0.002; 95% CI on the difference 0.237, 0.876), but also the XO ratio 1MU/1MX was significantly (P < 0.0001) increased from 1.34 +/- 0.09 to 2.24 +/- 0.14 (95% CI on difference 0.735, 1.059) due to a reduction of 1MX excretion. CONCLUSIONS: Substrates of OAT interact with renal excretion of caffeine metabolites and may falsify NAT2 and XO phenotyping results. Other phenotyping procedures, which are based on urinary metabolic ratios, should also be validated in this respect, especially in patients under polymedication.

Adult↗
PubMed2000

Effect of application volume of ethanol-isopropyl myristate mixed solvent system on permeation of zidovudine and probenecid through rat skin.

Permeation of zidovudine (AZT) and probenecid from an ethanol-isopropyl myristate (IPM) mixed system through rat skin was studied in a finite system. Several volume sizes of the ethanol-IPM mixed systems containing AZT and probenecid, both as suspensions, were applied on the skin of the hairless rat using a vertical glass cell, and the fractions of the drugs permeated in 8 hr Q%,8 hr were determined. For the systems containing 40% ethanol, the Q%,8 hr value decreased with the reduction of volume of the system applied, and the decreasing profile was similar to that calculated on the assumption that the permeability of the drug does not change with the volume of the sample applied. On the other hand, in the systems containing 10% or 20% ethanol, the Q%,8 hr value showed a maximum when a specific volume of the sample was applied. Therefore, the effect of sample volume on the Q%,8 hr value was different between the 40% ethanol-IPM system and the 10% or 20% ethanol-IPM system. Following pretreatment of the skin with 0.105 ml/cm2 of drug-free 40% ethanol-IPM for 2 hr, several volume sizes of 10% ethanol-IPM systems containing the drugs were applied on the skin to explain why the different profiles were observed in the system containing 10% or 20% ethanol. The results for pretreated skin suggest that the amount of ethanol in the systems with low ethanol concentration and small application volume is too small to exert an effect that enhances permeation of the drugs. In those systems, the integrated effect of ethanol on the skin would be important for the enhancing effect. Total volume, as well as concentration, of an enhancer should be set precisely in designing an efficient transdermal delivery system.

Administration, Cutaneous↗
PubMed1987

Macrophages possess probenecid-inhibitable organic anion transporters that remove fluorescent dyes from the cytoplasmic matrix.

We introduced several membrane-impermeant fluorescent dyes, including Lucifer Yellow, carboxyfluorescein, and fura-2, into the cytoplasmic matrix of J774 cells and thioglycollate-elicited mouse peritoneal macrophages by ATP permeabilization of the plasma membrane and observed the subsequent fate of these dyes. The dyes did not remain within the cytoplasmic matrix; instead they were sequestered within phase-lucent cytoplasmic vacuoles and released into the extracellular medium. We used Lucifer Yellow to study these processes further. In cells incubated at 37 degrees C, 87% of Lucifer Yellow was released from the cells within 30 min after dye loading. The dye that remained within the cells at this time was predominantly within cytoplasmic vacuoles. Lucifer yellow transport was temperature dependent and occurred against a concentration gradient; therefore it appeared to be an energy-requiring process. The fluorescent dyes used in these studies are all organic anions. We therefore examined the ability of probenecid (p-[dipropylsulfamoyl]benzoic acid), which blocks organic anion transport across many epithelia, to inhibit efflux of Lucifer Yellow, and found that this drug inhibited this process in a dose-dependent and reversible manner. Efflux of Lucifer Yellow from the cells did not require Na+ co-transport or Cl- antiport; however, it was inhibited by lowering of the extracellular pH. These experiments indicate that macrophages possess probenecid-inhibitable transporters which are similar in their functional properties to organic anion transporters of epithelial cells. Such organic anion transporters have not been described previously in macrophages; they may mediate the release of naturally occurring organic anions such as prostaglandins, leukotrienes, glutathione, bilirubin, or lactate from macrophages.

Adenosine Triphosphate↗
PubMed1976

The lack of effect of ampicillin plus probenecid given for genital infections with Neisseria gonorrhoeae on associated infections with Chlamydia trachomatis.

Forty-six men were successfully treated with a single oral dose of ampicillin (2 g) plus probenecid (1 g) for urethral infections with Neisseria gonorrhoeae. Chlamydia trachomatis was isolated from cultures of cells obtained from 11 of these men both before and after treatment; C. trachomatis was isolated from one man before but not after treatment and from three men after but not before treatment. No isolates were obtained from the remaining 31 men either before or after treatment. Of the 15 patients whose cultures yielded C. trachomatis, 12 developed postgonococcal urethritis; of the 31 patients from whose cultures no isolate was obtained, five developed postgonococcal urethritis. Of 44 women successfully treated with ampicillin plus probenecid for cervical infections with N. gonorrhoeae, 18 had C. trachomatis isolated from the cervix both before and after treatment. C. trachomatis was isolated from five women before but not after treatment and from two women after but not before treatment. No isolates were obtained from the remaining 19 women either before or after treatment. Thus ampicillin plus probencide in the dosage used rarely eliminated C. trachomatis from the genital tract of either men or women. Whereas men with a persisting chlamydial infection will probably develop postgonococcal urethritis and thus receive appropriate treatment, such an infection in women is not likely to be suspected unless attempts are made to isolate C. trachomatis.

Ampicillin↗
PubMed1983

Amoxycillin/clavulanic acid: the effect of probenecid.

The effect of probenecid on the combination of amoxycillin/clavulanic acid has been compared with the effect on amoxycillin alone and it has been shown that probenecid, whilst producing its expected effect on amoxycillin, did not affect the clavulanic acid concentration of the combination. A possible minor role for tubular secretion of clavulanic acid is discussed.

Adult↗
PubMedDate not supplied

A comparison of rosoxacin with ampicillin and probenecid in the treatment of uncomplicated gonorrhea.

Rosoxacin, a beta-lactamase-resistant, pyridyl quinolone derivative with in vitro activity against Neisseria gonorrhoeae, was compared to an oral regimen of ampicillin plus probenecid for the treatment of uncomplicated gonococcal infection. Fifty-seven patients were evaluated for the effectiveness of the two antibiotics. Thirty (97%) of 31 patients receiving rosoxacin were cured of their infection as were 25 (96%) of 26 patients who received the oral regimen of ampicillin plus probenecid. Both drug regimens were associated with a significant number of side effects. Of the ampicillin-treated group, 29% had diarrhea and/or abdominal cramping. Of the rosoxacin-treated patients, 52% had reactions classified as central nervous system effects; these included headaches, dizziness, euphoria, and drowsiness.

4-Quinolones↗
PubMed1988

Effect of maximal hydration on the renal responses to pretreatment with nonsteroidal anti-inflammatory drugs and probenecid in man.

The renal response to a challenge of maximal water diuresis has been studied in seven subjects pretreated over 48 h with either placebo, probenecid, indomethacin or piroxicam. Probenecid did not alter the excretion of water and sodium chloride when compared with placebo responses, but increased both phosphate and urate clearances. Indomethacin reduced significantly both water and sodium chloride clearances by approximately 40%. Piroxicam reduced water excretion to a similar extent but did not influence salt output. In parallel with these changes, both drugs caused significant phosphaturia. It is concluded that the renal actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are individually distinct and involve direct effects on tubular transport of ions and water to differing extents within both the proximal and distal portions of the nephron.

Adult↗
PubMed1995

The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid.

Ceftiofur sodium is a third-generation cephalosporin antibiotic. It is possible that non-steroidal anti-inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle. Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin. In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter. The organic anion transporter substrate used in this evaluation was probenecid. Ten healthy, non-pregnant, non-lactating dairy cows were used in a randomized complete three-way crossover design. In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus. For treatment with ceftiofur sodium alone, the mean volume of distribution at steady-state Vd(ss) was 0.2 +/- 0.06 L/kg, the mean volume of distribution by the area method Vd(area) was 0.38 +/- 0.22 L/kg, mean residence time (MRT) was 6.5 +/- 1.8 h, mean residence time in peripheral tissues (MRTp) was 2.6 +/- 1.0 h, total body clearance (Cl) was 0.032 +/- 0.013 L/kg/h and elimination rate constant (beta) was 0.097 +/- 0.044 h-1 (mean +/- standard deviation). No statistically significant changes were detected as a result of preceding treatment with aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Pharmacokinetics of ticarcillin and ticarcillin-probenecid in sheep.

Serum concentrations of ticarcillin were measured serially over a period of 12h in a cross over trial involving 6 healthy adult ewes after intravenous and intramuscular (IM) administration of 40 mg ticarcillin per kg body weight. Probenecid (40 mg/kg) was also administered IM immediately before the IM administration of 40 mg/kg ticarcillin. Pharmacokinetic values after intravenous administration were: half-life of elimination (T 1/2 beta) = 0.90 +/- 0.09 h; volume of distribution at steady state (Vdss) = 456.8 +/- 106.6 ml/kg, total body clearance (CIB) = 614.5 +/- 81.2 ml/h/kg. Ticarcillin persisted in serum at greater than or equal to 1.5 micrograms/ml for 4 hours. Pharmacokinetic and bioavailability values after intramuscular administration were: half-life of absorption (T 1/2 ab) = 8.08 +/- 1.98 min; T 1/2 beta = 0.96 +/- 0.07 h. Peak serum concentration (Cmax) was 31.11 +/- 6.02 micrograms/ml at 0.50 h (Tmax), bioavailability (F) was 0.82 +/- 0.09. After ticarcillin was administered IM together with probenecid the T 1/2 ab was 33.9 +/- 13.7 min, the T 1/2 beta 2.66 +/- 0.65 h, Cmax = 44.87 +/- 5.58 at 1.33 +/- 0.44 h, and F = 1.25 +/- 0.23.

Absorption↗