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PubMed2004

Evaluation and comparison of MRP1 activity with three fluorescent dyes and three modulators in leukemic cell lines.

MRP1 activity was evaluated and compared in 11 cell lines with different levels of MRP1 expression using functional assays of calcein acetoxymethyl ester (calcein-AM), carboxyfluorescein diacetate (CFDA) and Rhodamine 123 (Rh123) in combination with the modulators cyclosporin A (CsA), probenecid and MK571. A good correlation was found between MRP1 expression and the modulatory effect of MK571 on calcein-AM uptake (P = 0.01 and probenecid effect on CFDA uptake (P = 0.02). Additionally, the combined modulatory effect of MK571 and probenecid on CFDA uptake (P < 0.0001) and on calcein-AM uptake (P = 0.0001) were highly significant. No correlation was found between MRP1 expression and the effects of three modulators on Rh123 uptake or efflux. In conclusion, calcein-AM and CFDA uptake assays are the best choices to probe MRP1 activity and combination of two modulators may improve the efficiency of these assays.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Determination of folate transport pathways in cultured rat proximal tubule cells.

Deficiency of the vitamin folic acid has recently been linked with increased incidence of neural tube defects and of cardiovascular disease, through elevated plasma homocysteine levels. The kidney has an important role in conserving folate to counteract development of deficiency. Urinary folate excretion is regulated by the degree of reabsorption of folate by the proximal tubule cell. To evaluate an in vitro model for studies of the regulation of urinary folate excretion, the present studies examined the transport of 5-methyltetrahydrofolate (5-CH3-H4PteGlu), the primary form of folate in the glomerular filtrate, by normal rat proximal tubule (RPT) cells in confluent monolayer cultures. Specific binding of 5-CH3-H4PteGlu to the apical membrane was saturable (K(D) = 27 nM), but intracellular transport was not saturated up to 100 nM concentrations. 5-CH3-H4PteGlu transport was decreased 50% by concentrations of folic acid that completely blocked 5-CH3-H4PteGlu binding by the apical folate receptor. Probenecid (10 mM), an anion exchange (reduced folate carrier) inhibitor, reduced 5CH3-H4PteGlu transport by 50% without significantly affecting binding. Aspirin (3 mM) did not alter 5-CH3-H4PteGlu transport, but significantly enhanced the inhibition due to probenecid. Similarly, indomethacin (5 microM) potentiated the inhibition of 5-CH3-H4PteGlu transport by probenecid. These data suggest that RPT cells take up 5-CH3-H4PteGlu by both the folate receptor and the reduced folate carrier, implying a role for both pathways in regulating urinary folate excretion.

Animals↗
PubMed2000

Homeostatic role of the active transport in elimination of [3H]benzylpenicillin out of the cerebrospinal fluid system.

Cerebral acidic metabolites and penicillin are organic anions which can be carried by active transport into capillaries of the central nervous system (CNS). However, it is generally believed that these metabolites are mainly delivered from CNS to cerebrospinal fluid (CSF) and eliminated by CSF circulation over cortex and its absorption into dural venous sinuses. To test this hypothesis we studied fate of penicillin ([3H]benzylpenicillin) in the CSF under control conditions and when its active transport was blocked by probenecid. After application of penicillin into cisterna magna of control dogs, it is distributed only in traces to lumbar, ventricular and cortical CSF. However, when active transport of penicillin across capillary wall is blocked by probenecid, its disappearance from cisterna is slowed down and its distribution is greatly enhanced so that at 300 min penicillin concentrations in cisternal, lumbar and cortical CSF approach or equal each other. Disappearance of penicillin from cisternal CSF shows a single exponential course (half-time 30 min) in control, while in probenecid pretreated dogs this is a slow multiexponential process. The results indicate that the active transport across capillary wall in CNS, but not generally postulated unidirectional CSF circulation over cortex and its absorption into dural venous sinuses, is instrumental in elimination of cerebral acidic metabolites and in such a way homeostasis in brain and cerebrospinal fluid is maintained.

Animals↗
PubMed2000

Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system.

A novel non-competitive NMDA receptor antagonist MRZ 2/576 is a potent but rather short-acting (5-15 min) anticonvulsant following intravenous administration to mice as estimated by the prevention of maximal electroshock induced convulsions. This is most probably due to a rapid elimination of the drug from the central nervous system by transport processes that are sensitive to probenecid. Intravenous administration of the drug bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 prolongs the duration of the anticonvulsive activity in mice up to 210 min and after probenecid pre-treatment up to 270 min compared to 150 min with probenecid and MRZ 2/576 alone. The results of this study demonstrate that polysorbate 80 coated poly(butylcyanoacrylate) nanoparticles used so far as a delivery system to the brain for drugs that do not freely penetrate the blood brain barrier can also be used as a parenteral controlled release system to prolong the CNS availability of drugs that have a short duration of action.

Animals↗
PubMedDate not supplied

Nursing considerations in the use of cidofovir for CMV retinitis in patients with AIDS: report of a roundtable meeting.

Cytomegalovirus (CMV) retinitis, a late complication of infection with HIV, generally leads to blindness if untreated. Although the retinal damage from CMV cannot be reversed, disease progression can be arrested with any one of three antiviral agents, which must be continued indefinitely. Intravenous ganciclovir and foscarnet, the earliest therapies, must be administered every day and require placement of an indwelling catheter. Cidofovir, a newly introduced intravenous antiviral, requires the least frequent administration; after two once-a-week induction doses, maintenance therapy is given only once every other week. However, cidofovir is potentially nephrotoxic and must be coadministered with nephroprotective probenecid and saline hydration. Careful adherence to treatment administration guidelines for cidofovir and probenecid is essential for safe administration of both drugs. Averting and managing adverse reactions to cidofovir and probenecid may present a true nursing challenge; however, with proper patient selection and appropriate use, cidofovir has the potential to greatly enhance the quality of life of a patient with CMV retinitis.

AIDS-Related Opportunistic Infections↗
PubMed2002

Structure-effect relationship in the mobilization of cadmium in mice by several dithiocarbamates.

The structural characteristics of several dithiocarbamates (DTCs) [N-p-methylbenzyl-D-glucamine dithiocarbamate (MBGD), N-benzyl-D-glucamine dithiocarbamate (BGD), N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD) and N-p-carboxybenzyl-D-glucamine dithiocarbamate (CBGD)] that induce in vivo mobilization of cadmium (Cd) were examined in mice. The renal and hepatic contents of Cd were lower in the treatments with Cd-DTC combinations than in that with Cd alone. Probenecid pretreatment decreased the renal content of Cd in Cd-MBGD and Cd-BGD treated mice, but it increased the renal content of Cd and decreased the urinary excretion of the metal in Cd-HBGD and Cd-CBGD treated mice. Furthermore, although ureter-ligation did not affect the renal content of Cd in Cd-MBGD and Cd-BGD treated mice, it increased the renal content of Cd in Cd-HBGD and Cd-CBGD treated mice. These findings suggest that Cd-MBGD and Cd-BGD complexes are taken up into the tubular cells by an organic anion transport system through the basolateral membrane, whereas Cd-HBGD and Cd-CBGD complexes are secreted to the tubular lumen by an organic anion transport system through the brush border membrane. The results of probenecid pretreatment also led us to assume that the hepatic transport of these four Cd-DTC complexes is regulated, at least in part, by a probenecid-sensitive organic anion transport system.

Animals↗
PubMed2002

Methylmercury accumulation and fluxes across the intestine of channel catfish, Ictalurus punctatus.

The excised intestines of channel catfish, Ictalurus punctatus, were perfused at 20 or 4 degrees C for 1 h 45 min, with methylmercury (CH(3)HgCl) alone, or in the presence of excess L-cysteine (L-Cys), D-cysteine (D-Cys), L-methionine (L-Met); or with ouabain or probenecid to identify the potential CH(3)Hg(II) uptake pathways in fish intestines. A temperature effect was noted, with CH(3)Hg(II) concentrations in tissues perfused at 20 degrees C being higher than at 4 degrees C, substantiating the idea that mechanisms requiring metabolic energy are involved in CH(3)Hg(II) uptake in fish intestines. The results indicate that, when CH(3)Hg(II) is complexed as the CH(3)Hg-L-Cys complex, it is taken up via an L-neutral amino acid carrier and rapidly transported to the serosal side of the intestine. Methylmercury uptake could be inhibited by probenecid and ouabain, although probenecid had less impact on CH(3)Hg(II) uptake than ouabain. Our results for CH(3)Hg(II) uptake in the presence of D-Cys, L-Met in excess of L-Cys, or with a metal mixture further established that CH(3)Hg(II) uptake across fish intestines occurs via a variety of pathways, including an energy-dependent L-neutral amino acid carrier, and that the route and amount of accumulation were a function of CH(3)Hg(II) speciation in the digestive tract of the fish.

Animals↗
PubMed1996

Kinetics of quinolone antibiotics in rats: efflux from cerebrospinal fluid to the circulation.

PURPOSE: An active transport system, which pumps quinolone antimicrobial agents (quinolones) from cerebrospinal fluid (CSF) to systemic blood, exists at the choroid plexus, an epithelial tissue that forms the blood-CSF barrier (BCSFB). The present study was carried out to clarify the contribution of this transport system to the disposition of quinolones in the central nervous system. METHOD: Six quinolones were administered intracerebroventricularly to rats and their elimination from the CSF was examined. The inhibitory effect of probenecid and quinolones on the efflux of fleroxacin from the CSF was also examined. Probenecid or two types of quinolone (AM-1155, pefloxacin) were co-administered intracerebroventricularly with fleroxacin. RESULTS: The elimination clearance from the CSF for norfloxacin, AM-1155, fleroxacin, ofloxacin, sparfloxacin and pefloxacin was 14, 22, 21, 20, 47 and 35 microliters/min/rat, respectively. An approximately 3.5-fold difference was thus observed between norfloxacin and sparfloxacin. These values were 4- to 14-fold larger than the [14C]mannitol clearance. Furthermore, the elimination clearance of quinolones from the CSF was 7- to 60-fold larger than the active efflux clearance at the BCSFB estimated from our previous in vitro data. Co-administration of AM-1155, pefloxacin and probenecid did not inhibit the elimination of fleroxacin from the CSF. CONCLUSIONS: The active transport system at the BCSFB plays only a small part in the elimination of quinolones from the CSF. Passive diffusion via the BCSFB and diffusion across the ependymal surface into brain extracellular fluid, followed by efflux across the blood-brain barrier, may be the predominant pathway for quinolone elimination from the CSF.

4-Quinolones↗
PubMed1980

Renal tubular secretion and effects of furosemide.

Continuous intravenous infusion of furosemide (8 mg/hr) to 6 healthy subjects induced an average diuresis at steady state of 667 +/- 144 ml/30 min (+/- SD) with a mean plasma concentration of furosemide of 623 +/- 209 ng/ml. The urinary output of Cl- was 50.4 +/- 7.5, of Na+ 47.7 +/- 8.7, and of K+ 5.4 +/- 0.6 mmole/30 min. Intravenous injection of probenecid (1 gm) raised the plasma furosemide level to a maximum of 1,584 +/- 151 ng/ml. Despite this, the urinary excretion of water, Cl-, Na+, and K+ decreased to 52%, 39%, 39%, and 52%, respectively, of control values. Probenecid greatly reduced the urinary excretion and renal clearance of furosemide. There was no or negative correlation between the plasma levels of furosemide and its diuretic and saluretic effects. The urinary excretion and renal clearance of the diuretic correlated positively with these effects. No effect of probenecid on protein binding of furosemide was detected. The findings show that the diuretic effects of furosemide depend on active tubular secretion of the drug and thus on its tubular fluid concentration.

Adult↗
PubMed1983

Coupling between renal tubular secretion and effect of bumetanide.

The relationship between renal tubular secretion of bumetanide and its saluretic effect was studied in six healthy subjects before and after probenecid (1 gm IV). Bumetanide was determined in serum and urine by HPLC. Continuous intravenous infusion of bumetanide (200 micrograms/hr) gave an average diuresis at steady state of 15 +/- 3 ml/min. Corresponding plasma concentration, urinary excretion rate, and renal clearance of bumetanide averaged 14.3 +/- 2.3 ng/ml, 64 +/- 31 micrograms/30 min, and 145 +/- 59 ml/min. After probenecid there was a marked change in bumetanide kinetics. Average plasma concentration rose to 41.7 +/- 8.1 ng/ml, whereas renal clearance and urinary excretion rate fell to 15.1% and 29.5% of control. There was also a concomitant decrease in diuresis and saluresis to 47% and about 40% of control. Probenecid also reduced the renal clearance of para-aminohippurate and inulin to 67% and 75% of control. Since the fractional water and sodium chloride excretion was also reduced about 33% and 42%, it is concluded that a large part of the diuretic effect of bumetanide depends on its active tubular secretion. As with furosemide and piretanide, bumetanide diuresis is elicited from the luminal side of the human nephron.

Adult↗
PubMed1983

Renal handling of the monobactam azthreonam in healthy subjects.

Azthreonam is a new completely synthetic, monocyclic beta-lactam antibiotic with potent activity in vitro against most gram-negative aerobic bacteria. Its renal handling was studied in six healthy men after an intravenous loading dose of 1200 mg over 2 min followed by a continuous infusion of 500 mg/hr for 4 hr with and without oral probenecid (1 gm b.i.d. for 2 days before azthreonam infusion and during the day of infusion). To assess glomerular filtration, each subject also received an intravenous loading dose and continuous infusion of inulin. Azthreonam was excreted in the urine by glomerular filtration and tubular secretion in essentially equal proportions. Probenecid reduced plasma clearance of azthreonam bY suppressing renal tubular secretion, without altering glomerular filtration rate or nonrenal elimination. Probenecid increased total and free azthreonam levels and the azthreonam plasma t1/2 while reducing plasma protein binding and the apparent steady-state volume of distribution.

Administration, Oral↗
PubMed1993

A protein with anion exchange properties found in the kidney proximal tubule.

One important mechanism for reabsorption of chloride in the kidney proximal tubule involves anion exchange of chloride for a base. Anion exchange transport systems in general demonstrate sensitivity to inhibition by disulfonic stilbenes, probenecid, furosemide, and the arginyl amino group modifier phenylglyoxal. Using disulfonic stilbene affinity chromatography, we have identified and partially purified a protein with anion exchanger properties in luminal membrane vesicles isolated from rabbit kidney cortex. This protein has a molecular weight of 162 kD. The binding of the 162 kD protein to the stilbene affinity matrix is inhibited by disulfonic stilbenes, probenecid, furosemide, and phenylglyoxal. Reconstitution of the proteins eluted from the affinity matrix into liposomes demonstrates anion exchange activity as assayed by radiolabeled chloride influx. Deletion of the 162 kD protein from the eluted mixture by probenecid diminishes the anion exchanger activity in the reconstituted liposomes. Further purification of the disulfonic stilbene column eluant by Econo-Pac Q ion exchange chromatography resulted in significant enrichment in 162 kD protein abundance and also anion exchange activity in reconstituted liposomes. The results of the above experiments strongly suggest that the 162 kD protein is an anion exchanger. Insight into the functional and molecular characteristics of this protein should provide important information about the mechanism(s) of chloride reabsorption in the kidney proximal tubule.

Animals↗
PubMed1996

Plasma clearance in the rat of a furan dicarboxylic acid which accumulates in uremia.

The furan dicarboxylic acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and has been implicated in several aspects of the uremic syndrome: the defective binding of organic acids in uremic plasma, inhibition of active tubular secretion, anemia and the severity of neurological symptoms. Evidence from experiments with rat kidney slices suggests that 5-propyl FPA undergoes active tubular secretion, and so its clearance after an intravenous bolus dose (5 mg/kg; 21 mumol/kg) was investigated in anaesthetized female Wistar albino rats in vivo. The effects of intravenous bolus doses of p-aminohippuric acid (PAH) and probenecid on the clearance of this dose of 5-propyl FPA were also studied. The mean values (N = 16) for plasma half-life, plasma clearance and apparent volume of distribution of 5-propyl FPA were 3.6 hours, 2.4 ml . min(-1) . kg(-1) and 0.69 liter . kg(-1), respectively. An equimolar dose of PAH did not affect the clearance of 5-propyl FPA, but a tenfold higher molar dose of PAH (40.4 mg/kg) increased the area under the plasma-concentration time curve of 5-propyl FPA, and there was a trend towards a decrease in the clearance and a prolongation of the half-life. Probenecid at a fivefold higher dose than 5-propyl FPA had a similar effect to PAH and increased the AUC of 5-propyl FPA. PAH and probenecid decreased the plasma clearance of 5-propyl FPA, which is evidence that this uremic metabolite undergoes active tubular secretion. It follows that 5-propyl FPA could therefore inhibit the secretion of other organic acids.

Animals↗
PubMed2001

Effect of acetazolamide on outward permeability of blood-retina barrier using differential vitreous flyorophotometry.

PURPOSE: To measure fluorescein (F) and fluorescein monoglucuronide (FG) concentrations in the vitreous and evaluate the effect of acetazolamide (AZM) on the outward permeability of the blood-retina barrier (BRB) using differential vitreous fluorophotometry (DVF). METHODS: DVF was performed 180 minutes after intravenous injection of AZM (5 mg/kg) and 50 mg of sodium fluorescein in six rabbits (AZM group). DVF also was performed in six rabbits injected intravenously with only 50 mg of sodium fluorescein (control group). The F/FG ratio was calculated based on the concentrations of F and FG obtained by DVF. DVF also was performed 180 minutes after 50 mg of intravenous injection of sodium fluorescein in five rabbits given probenecid (150 mg/kg) intraperitoneally (probenecid group). RESULTS: The average F/FG ratio was 0.36 +/- 0.17 (range, 0.22-0.66) in the AZM group, which was significantly smaller than the control value of 0.74 +/- 0.22 (range, 0.50-1.60). The average F/FG ratio at 180 minutes after injection was 1.51 +/- 0.46 (range, 0.94-2.00) in the probenecid group, which was significant higher (p < 0.05) than that of the AZM or control group. CONCLUSIONS: This study showed that the F/FG ratio might be a good indicator of the estimated outward permeability of the BRB using DVF and that AZM may accelerate the outward active transport function of the BRB.

Acetazolamide↗
PubMedDate not supplied

Penetration of cefoxitin into cerebrospinal fluid and treatment of meningitis caused by gram-negative bacteria.

Two patients with meningitis caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae were treated successfully with intravenous cefoxitin plus oral probenecid. A total of 25 patients with central nervous system disorders that required a diagnostic spinal tap were also given cefoxitin, with or without probenecid, for determination of the degree of penetration into cerebrospinal fluid. In patients with uninflamed meninges, little or no cefoxitin entered after a single dose of 4-6 g. After three doses of 4 g each over a 6-8-hr period, penetration was considerable (average, 7% of the simultaneous serum level). In patients with inflamed meninges, a similar concentration was achieved rapidly after a single 2-g dose. After a day of therapy, cerebrospinal fluid levels equivalent to 30%-70% of the simultaneous serum levels were found; as the inflammation subsided, cerebrospinal fluid levels fell to around 15% of those in serum. Probenecid did not appear to influence greatly the degree of penetration.

Adolescent↗
PubMedDate not supplied

Treatment of uncomplicated gonorrhea with cefotaxime.

Three hundred seventy-six patients with uncomplicated infection due to beta-lactamase-negative Neisseria gonorrhoeae were treated with 1.0 g of cefotaxime intramuscularly or with 4.8 x 10(6) units of aqueous procaine penicillin G (APPG) intramuscularly plus 1.0 g of probenecid, administered orally. Cefotaxime eradicated 157 (98.1%) of 160 urethral or endocervical gonococcal infections, 22 (96%) of 23 rectal infections, and 8 (73%) of 11 pharyngeal infections. In comparison, APPG-probenecid eradicated 125 (98.4%) of 127 urethral or endocervical gonococcal infections, 17 (94%) of 18 rectal infections, and 4 (100%) of 4 pharyngeal infections. Of 304 domestic beta-lactamase-negative gonococcal isolates, 294 (96.7%) were inhibited by less than or equal to 0.03 microgram/ml of cefotaxime. In a separate study, cefotaxime eradicated 31 of 31 urethral infections due to beta-lactamase-positive strains of N. gonorrhoeae acquired by U.S. Navy personnel in the Philippines. Treatment with cefotaxime was tolerated better than treatment with APPG, primarily because only one injection is required for cefotaxime. The efficacy of cefotaxime was comparable to that of APPG-probenecid in the treatment of uncomplicated genital or rectal infection due to beta-lactamase-negative N. gonorrhoeae, and cefotaxime appears to be highly effective for the treatment of urethral infection due to beta-lactamase-positive N. gonorrhoeae. Further studies are needed for assessment of the efficacy of cefotaxime for treatment of pharyngeal gonococcal infection.

Cefotaxime↗
PubMed1992

J774 macrophages secrete antibiotics via organic anion transporters.

Mouse macrophages and J774 macrophage-like cells express probenecid-inhibitable organic anion transporters that remove anionic dyes from the cells' cytoplasmic matrix and secrete these dyes into the extracellular medium. The present studies show that these transporters also secrete antibiotics from J774 macrophages. Penicillin G permeates J774 cells poorly, but after it was introduced into the cell cytoplasm, it was secreted in a probenecid-inhibitable fashion. The quinolone norfloxacin enters macrophages readily. Probenecid retarded the secretion of intracellular norfloxacin by J774 cells and enhanced norfloxacin accumulation three- to fourfold. Thus the intracellular accumulation of norfloxacin is regulated in part by organic anion transporters that secrete norfloxacin (and penicillin G) from J774 cells. This transport process may have clinical significance, as fluoroquinolones inhibit growth of intracellular pathogens such as mycobacteria and Brucella organisms in vitro but fail to arrest infections with these organisms in vivo.

Adenosine Triphosphate↗
PubMed1996

Folate transport pathways regulate urinary excretion of 5-methyltetrahydrofolate in isolated perfused rat kidney.

The reabsorption of 5-methyltetrahydrofolic acid (5-CH3-H4PteGlu) by the renal proximal tubule has an important role in the maintenance of plasma folate concentrations. However, the mechanism by which this vitamin traverses the renal epithelium remains to be determined. Studies in cultured cells have suggested that the folate receptor in association with a probenecid-sensitive anion carrier may be involved in the transmembrane transport of the vitamin. Because 5-CH3-H4PteGlu is reabsorbed and metabolized in the isolated perfused rat kidney (IPRK) in a smaller manner to in vivo models, the IPRK was used to evaluate pathways involved in folate reabsorption. Reabsorption of 5-CH3-H4PteGlu could not be saturated in the isolated perfused rat kidney, even at concentrations up to 2 mumol/L. Folic acid (PteGlu) was used as a competitive inhibitor of FR-dependent reabsorption of 5-CH3-H4PteGlu. When 5-CH3-H4PteGlu was maintained at 1 nmol/L (a concentration at which receptor-mediated transport should be maximal), PteGlu (up to 100 nmol/L) had no effect on reabsorption. The addition of probenecid (1 mmol/L) did not affect the reabsorption of 5-CH3-H4PteGlu but inhibited the fractional excretion of the anion para-aminohippurate. Probenecid also inhibited the urinary excretion of 5-CH3-H4PteGlu metabolites, indicating that reabsorbed 5-CH3-H4PteGlu was metabolized to products that were subsequently secreted into the urine by anion exchange pathways. The physiological importance of a folate receptor-mediated reabsorption of 5-CH3-H4PteGlu appears to be minor in the isolated perfused rat kidney, whereas nonspecific pathways appear to play a major role in the renal folate reabsorption.

Analysis of Variance↗