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PubMed1992

Specificity of basolateral organic anion exchanger in proximal tubule for cellular and extracellular solutes.

We used an epifluorimetric technique to study the mechanism of organic anion transport across the basolateral surface of isolated S2 segments of rabbit proximal tubules. Fluorescein influx and efflux rates across the basolateral surface of lumen-collapsed tubules were determined from serial measurements of cellular fluorescein content after its addition to or removal from the bathing medium. We examined the effect on fluorescein transport of monocarboxylic and dicarboxylic metabolic intermediates added to the bathing medium or preloaded into the cells. The presence of the monocarboxylates (octanoate, valerate, butyrate, propionate, and acetate) in the bathing medium inhibited fluorescein influx. The eight-carbon-chain fatty acid, octanoate, was nearly as potent an inhibitor as probenecid and was more potent than p-aminohippurate (PAH) (IC50 = 10, 6, and 141 microM, respectively); the shorter chain fatty acids were much less effective (IC50 greater than or equal to 1,000 microM). The dicarboxylates (succinate, adipate, and alpha-ketoglutarate) moderately inhibited fluorescein influx (IC50 = 505, 245, and 257 microM, respectively). To determine the effect of intracellular organic anions on fluorescein influx, tubules were preincubated with organic anions to load the cells; the compounds were then removed from the bath, and fluorescein influx was measured. Preincubation with monocarboxylates, octanoate, butyrate, acetate, and PAH had no effect. In contrast, the dicarboxylates alpha-ketoglutarate, glutarate, and adipate stimulated fluorescein influx by 58, 53, and 43%, respectively, but succinate had no effect. Fluorescein efflux was accelerated by medium octanoate, PAH, alpha-ketoglutarate, and succinate but not by acetate. Probenecid alone had no effect on fluorescein efflux, but it blocked the stimulation caused by medium PAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Tissue concentration and urinary excretion pattern of sulfofluorescein by the rat kidney.

In order to find a fluorescein analog that is excreted in a way similar to p-aminohippurate (PAH) and is suitable to register excretion into the urine and also to monitor continuously the concentration within cortical tissue, the interference of fluorescein, sulfofluorescein (SF), and fluorescein-5(6)-sulfonate with the contraluminal transport systems of PAH, succinate, and sulfate and with the luminal transport system of sulfate and lactate was evaluated. All three substances exerted a strong inhibitory potency against contraluminal PAH uptake (apparent Ki, 0.06 to 0.1 mmol/L) and also showed a moderate to small inhibitory potency against contraluminal sulfate transport (apparent Ki, 0.7 to 5.3 mmol/L). None of the three substrates interacted with the contraluminal dicarboxylate transport. Luminally, fluorescein and SF interacted with the lactate transporter (apparent Ki, approximately 3.0 mmol/L), whereas SF and fluorescein-5(6)-sulfonate had a very weak inhibitory potency against luminal sulfate transport (apparent Ki, 30 to 40 mmol/L). Because of its relatively low interference with the contraluminal sulfate transport, we preferred SF in the following study (protein binding, 88%) over fluorescein-5(6)-sulfonate (protein binding, 43.3%) and fluorescein (protein binding, 77.3%). A bolus injection of SF was given together with [14C]inulin into the jugular vein to rats in mannitol diuresis. Excretion of both substances in the urine was measured in 5-min samples. Fluorescence of the kidney surface was monitored at the exposed kidney with a photocell (excitation light, 470 nm; emission light, 530 nm). The effect of interfering substances was evaluated by their application 1 min before, simultaneously, or 1 min after SF bolus injection. PAH < probenecid < apalcillin inhibited SF excretion in the urine and, to a similar degree, SF fluorescence in cortical tissue. Inhibition was strongest when the substances were given simultaneously with SF. With the injection of alpha-ketoglutarate, glutarate, and succinate, an increase of SF excretion in the urine and, partially also, of SF content in tissue was seen. Tetrafluorosuccinate and mercaptosuccinate inhibited urinary SF excretion and tissue fluorescence strongly. Therefore, SF secretion is completely inhibited whereas filtration remained unaffected. The injection of acetate, lactate, and pyruvate as well as of 2-chloropropionate and thiosulfate did not change urinary excretion and tissue fluorescence of SF significantly. In SF-preloaded animals, the injection of probenecid, apalcillin, tetrafluorosuccinate, and mercaptosuccinate caused an immediate decrease of cellular SF content, whereas the injection of glutarate caused an increase. SF fluorescence in tissue was linearly related to urinary excretion of SF, whereas urinary excretion of inulin was barely affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir.

Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir and adefovir are dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of both drugs are independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and both drugs are cleared by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir and adefovir from serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For both drugs, > 90% of an intravenous dose is recovered unchanged in the urine over 24 hours. Metabolism does not contribute significantly to the total clearance of either drug. Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity, presumably by blocking its active tubular secretion. This is the basis of the clinical use of concomitant probenecid as a nephroprotectant during cidofovir therapy. Subcutaneous administration produces exposure equivalent to that following intravenous administration. Drug interaction studies with cidofovir are ongoing, but there is no evidence of an interaction between zidovudine and either cidofovir or adefovir. Clearance of cidofovir in patients with renal impairment showed a linear relationship to creatinine clearance. The low oral bioavailability of adefovir has led to the development of an oral prodrug, adefovir dipivoxil, currently in development for the treatment of HIV and hepatitis B infections.

Adenine↗
PubMed1985

Renal transport of gossypol in the rabbit.

The present work was carried out to investigate the transport characteristics of gossypol, a toxic weak organic acid (pK = 7.2) contained in cottonseed, into the rabbit renal cortical slice. The uptake of gossypol increased linearly during a 2-hr incubation after which it leveled off with the average slice-to-medium concentration ratio (S/M) slightly above 20. In the presence of metabolic inhibitors, the S/M gossypol leveled off at about 9, suggesting an extensive binding of gossypol to tissue proteins. The uptake of gossypol was significantly inhibited by p-aminohippurate (PAH), probenecid, ouabain, and DIDS, all of which are known inhibitors of renal organic anion transport. However, the gossypol uptake was not affected by tetraethylammonium (TEA), a prototypical organic cation. Kinetic studies indicated that the apparent Km for gossypol transport is 0.28 mM, and also that probenecid inhibits gossypol transport in a competitive manner. It is concluded that gossypol is transported by the renal tubule through the classic organic anion system.

2,4-Dinitrophenol↗
PubMed1986

Lack of interaction between atrial natriuretic factor and renal organic anion transport system.

The aim of the present investigation was to test the hypothesis that atrial natriuretic factor (ANF) is secreted into the proximal tubule lumen by the organic anion transport mechanism. The rationale for this hypothesis was the reported probenecid attenuation of the natriuretic effect of ANF. Probenecid is widely regarded as an inhibitor of organic acid transport in the proximal tubule. ANF was prepared in varying degrees of purity ranging from a relatively crude extract to a highly purified form. A commercially available form was also used. All forms were bioassayed using the anesthetized rat and a diuresis and natriuresis was observed in each case which was comparable to literature reports. Interaction of ANF with the organic acid transport system was evaluated using the renal cortical slice technique. Over a wide range of concentrations, there was no effect of ANF on cortical slice accumulation of either p-aminohippurate (PAH), the classical substrate of the organic anion transport system or tetraethylammonium (TEA), a typical organic cation. It is concluded that although ANF may indeed exert its effect at the luminal membranes of the nephron, access to the lumen is not mediated by the organic cation or anion transport system in the proximal tubule.

Aminohippuric Acids↗
PubMed1981

Treatment of bacterial meningitis in children without intravenous fluids.

It would be easier and cheaper, and there would be less risk of cerebral oedema, if bacterial meningitis could be adequately treated without the intravenous administration of fluid. Fifty children with bacterial meningitis were treated with intramuscular injections of benzyl penicillin, probenecid given orally and chloramphenicol palmitate suspension given orally, and the outcome was evaluated prospectively. Seven (14%) of the 50 children died. In a control group of 50 children with bacterial meningitis treated with the intravenous administration of benzyl penicillin and chloramphenicol sodium succinate, the outcome was determined retrospectively. Twelve (24%) of the 50 children died. The difference in mortality rate was 10% +/- 15.7% (+/- 2 SE), which is not significant. Except in the rare case of a child with shock or persistent vomiting, bacterial meningitis can be effectively treated with six-hourly intramuscular injections of penicillin, and probenecid and chloramphenicol given orally.

Administration, Oral↗
PubMed1976

Treatment of uncomplicated gonorrhea with Polycillin-PRB.

Penicillin has remained the choice drug for the treatment of gonorrhea. Its cure rate has been relative, and because cure rates are not as good as one would wish, an additional increase in dosage has been advised. Despite an improved cure rate with increased dosages, we are rapidly approaching a dose requirement beyond that which can be administered practically on an outpatient basis. Therefore other antimicrobial agents have been evaluated for the treatment of gonorrhea. Ampicillin 2 gm (IM) with 1 gm probenecid was evaluated in 1969 with a 99% plus cure rate. It also has been found that 3.5 gm of ampicillin orally (7 capsules of 500 mg) and probenecid (2 tablets of 500 mg) is an effective treatment for gonorrhea. We undertook the present study to evaluate the efficacy of a new single oral combination treatment, Polycillin-PRB.

Adolescent↗
PubMed1999

Active lucifer yellow secretion in renal proximal tubule: evidence for organic anion transport system crossover.

Recent studies show that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Here we investigated the possibility that organic anions entering the cells on one system can exit into the lumen on a transporter associated with the other system. In isolated rat kidneys perfused with 10 microM lucifer yellow (LY, a fluorescent organic anion) plus 100 micrograms/ml inulin, the LY-to-inulin clearance ratio averaged 1.6 +/- 0.2, indicating net tubular secretion. Probenecid significantly reduced both LY clearance and LY accumulation in kidney tissue. In intact killifish proximal tubules, confocal microscopy was used to measure steady-state LY uptake into cells and secretion into the tubular lumen. Probenecid, p-aminohippurate, and ouabain nearly abolished both uptake and secretion. To this point, the data indicated that LY was handled by the sodium-dependent and ouabain-sensitive organic anion transport system. However, leukotriene C4, an inhibitor of the luminal step for the sodium-independent and ouabain-insensitive organic anion system, reduced luminal secretion of LY by 50%. Leukotriene C4 did not affect cellular accumulation of LY or the transport of fluorescein on the sodium-dependent system. A similar inhibition pattern was found for another fluorescent organic anion, a mercapturic acid derivative of monochlorobimane. Thus, both organic anions entered the cells on the basolateral transporter for the classical, sodium-dependent system, but about half of the transport into the lumen was handled by the luminal carrier for the sodium-independent system, which is most likely the multidrug resistance-associated protein. This is the first demonstration that xenobiotics can enter renal proximal tubule cells on the carrier associated with one organic anion transport system and exit into the tubular lumen on multiple carriers, one of which is associated with a second system.

Animals↗
PubMed2003

An artificial amino acid, 4-iodo-L-meta-tyrosine: biodistribution and excretion via kidney.

UNLABELLED: We evaluated the use of radiolabeled 4-iodo-L-meta-tyrosine as an amino acid transport marker. The pharmacologic features of this compound, particularly the biodistribution and excretion, were examined by conducting in vivo and in vitro studies using 4-(125)I-iodo-L-meta-tyrosine (4-(125)I-mTyr). Results obtained for L-(14)C-Tyr and 3-(125)I-iodo-alpha-methyl-L-tyrosine ((125)I-IMT) were used for comparison. METHODS: In vivo biodistribution studies of 4-(125)I-mTyr were performed in male ddY mice. Urinary excretion of 4-(125)I-mTyr and (125)I-IMT with administration of probenecid was studied. Local distribution of 4-(125)I-mTyr and (125)I-IMT in kidney was visualized by autoradiography. We performed metabolite analysis of 4-(125)I-mTyr in mice. For in vitro studies, reabsorption mechanisms of 4-(125)I-mTyr were compared with those of (125)I-IMT and the parent L-(14)C-Tyr using superconfluent monolayers of the porcine kidney epithelial cell line LLC-PK(1) in medium containing inhibitor (L-Tyr, D-Tyr, and 2,4-dinitrophenol), in Na(+)-free medium, and at 4 degrees C. RESULTS: 4-(125)I-mTyr demonstrated high accumulation in the pancreas and kidney and comparable brain uptake to that of (125)I-IMT. Blood clearance of 4-(125)I-mTyr was faster than that of (125)I-IMT. Three hours after administration, >70% of 4-(125)I-mTyr was excreted via the urine, whereas <5% was found in the feces. Renal autoradiography revealed moderate accumulation of 4-(125)I-mTyr and high accumulation of (125)I-IMT in the renal cortex. Probenecid further reduced accumulation of 4-(125)I-mTyr and (125)I-IMT in the kidney as well as urinary excretion. At 30 min after tracer injection, intact free 4-(125)I-mTyr accounted for >98.1% of the total present in kidney and >96.3% in urine. Protein incorporation was not observed. Uptake of 4-(125)I-mTyr into LLC-PK(1) cell monolayers was remarkably reduced by 5 mmol/L L-Tyr (4.6%) and incubation at 4 degrees C (15.6%) but was reduced by 5 mmol/L D-Tyr (50.0%). L-(14)C-Tyr and (125)I-IMT showed similar results; however, uptake of (125)I-IMT was enhanced by 0.1 mmol/L 2,4-dinitrophenol (165.1%), an inhibitor of generation of energy-rich phosphates. CONCLUSION: The artificial amino acid 4-(125)I-mTyr demonstrated high metabolic stability, rapid blood clearance, rapid urinary excretion, and similar biodistribution to other radiolabeled L-Tyr analogs. 4-(125)I-mTyr can be a competitive substrate of L-Tyr reabsorption. However, 4-(125)I-mTyr demonstrates different pharmacologic features than those of (125)I-IMT, particularly in renal handling. 4-(125)I-mTyr may potentially be applied as a new amino acid transport marker.

Amino Acids↗
PubMed1976

Transport of organic cations and anions by choroid plexus.

The accumulation of organic cations and anions by the isolated rabbit choroid plexus was measured and the results were considered in comparison to in vivo measurements of transport using the ventriculocisternal perfusion technique also in rabbits. The accumulation in vitro of 3H-p-aminohippurate (PAH) and 14C-N1-methylnicotinamide (NMN) was shown to be organic anion and cation specific and dependent upon oxidative metabolism since tissue/medium ratios were reduced by competitive inhibitors including dibenamine and mepiperphenidol for cation transport and probenecid for anion transport and were also reduced by cyanide and dinitrophenol. Rabbits pretreated with chlorpromazine and anesthetized with pentobarbital were perfused lateral ventricle to cisterna magna with artificial cerebrospinal fluid containing inulin, 3H-PAH and 14C-NMN. Ratios of concentrations of these substances in the perfusate to those infused were calculated. Significant reductions in the ratios for PAH and NMN compared to unulin were obtained when low rates of perfusion, 40mul/min, were employed with low concentrations of PAH (2 mug/ml) and NMN (0.2 mug/ml). Probenecid (10(-3)M) specifically increased the ratio for PAH without affecting the NMN ratios. Mepiperhenidol (10(-o) M) blocked NMN transport but no PAH. The data and calculated clearances indicate that these prototype anions and cations may be actively transported out of cerebrospinal fluid, but for cations only at a low rate.

Aminohippuric Acids↗
PubMed1992

Organic cation transport and cationic drug interactions in freshly isolated proximal tubular cells of the rat.

Freshly isolated proximal tubular cells (PTC) of the rat are used to study the uptake of a prototypical organic cation, tetraethylammonium (TEA), and the influence of other cationic drugs on TEA uptake. The time dependency of 50 microM TEA uptake was determined by incubating PTC for time periods from 10 sec until 60 min. TEA uptake was linear for at least 2 min and reached equilibrium after 30 min. The cell to medium ratio reached a value of 8 after 60 min, indicating marked accumulation of TEA. TEA uptake was concentration dependent and saturable, with an apparent Km of 63 +/- 7 microM and Vmax of 0.57 +/- 0.02 nmol/mg protein.min. In comparison with cells cultured on filters, the overall transport characteristics of TEA in PTC seem to resemble basolateral to apical flux. The concentration-dependent inhibition of some H2 antagonists and various cations on 32 microM TEA uptake was investigated, as well as the interaction with probenecid. Analysis of the log-concentration inhibition curves showed that mepiperphenidol, trimethoprim, famotidine and cimetidine had a high and low IC50 value, whereas ranitidine, nizatidine, cimetidine sulfoxide, N1-methylnicotinamide and probenecid had only a low IC50 value. The data reported here are comparable with those from other preparations, and it is possible to extrapolate to the human in vivo situation. Moreover, the isolation procedure is relatively simple and quick and the yield is high.

Animals↗
PubMed1976

National gonorrhea therapy monitoring study: adverse drug reactions.

The Center for Disease Control and cooperating clinics monitored adverse drug reactions in 6,969 patients who were treated for suspected uncomplicated gonorrhea with one of the four 1972 United States Public Health Service (USPHS) recommended regimens and returned for reexamination. Of those patients receiving the aqueous procaine penicillin G (APPG)-probenecid regimen, 2.0% had at least one adverse reaction and 0.18% experienced procaine reactions. No life-threatening reactions occurred. The overall reaction rates for the ampicillin-probenecid, tetracycline and spectinomycin regimens were 0.62%, 5.9%, and 0.61%, respectively. Our findings document the relative safety of the USPHS recommended regimens.

Drug Administration Schedule↗
PubMedDate not supplied

The effect of serotonin receptor blocking agents--cyproheptadine and danitracen--on serotonin turnover in the rat brain.

Cyproheptadine (CPH), 0.5 mg/kg ip, did not affect the cerebral serotonin (5-HT) level, but elevated the level of 5-hydroxyindoleacetic acid (5-HIAA). Danitracen (DN), 1 mg/kg ip, depressed the cerebral 5-HT level and elevated the 5-HIAA level, but at a dose 10 mg/kg did not affect the levels of either the amine, or its metabolite. Both CPH and DN, 1 mg/kg, significantly potentiated the disappearance of 5-HT after administration of p-chlorophenylalanine. DN, in a low dose, accelerated the disappearance of 5-HT after inhibition of 5-HT synthesis by alpha-propyldopacetamide. The rate of accumulation of 5-HIAA after probenecid, was increased only by CPH. CPH did not affect the 5-HT accumulation after pargyline, while DN depressed its accumulation. The results of experiments on the levels of 5-HT and 5-HIAA, and on the rate of disappearance of 5-HT after inhibition of tryptophan decarboxylase suggest that CPH and DN increase the 5-HT turnover. The results of studies on the turnover rate of 5-HT after administration of probenecid and parygline do not corroborate fully this assumption. Possibly, this discrepancy may depend on differences in the action of 5-HT in various brain areas and interaction of serotoninolytics tested with effects of the MAO inhibitor.

Amides↗
PubMed2004

ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages.

OBJECTIVES: To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. DESIGN: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes. METHODS: P-gp and MRP expression in response to long-term zidovudine (3'-azido-3'-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp. RESULTS: Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp. CONCLUSION: AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1992

Transport of salicylic acid through monolayers of a kidney epithelial cell line (LLC-PK1).

LLC-PK1 cells were used as a model of renal proximal epithelium to study the nonionic diffusion of salicylic acid (SAL). The apparent [14C]SAL transcellular permeability (PSal) and intracellular content were estimated at 20-21 degrees C from fluxes measured across cell monolayers grown on filters, in both apical-to-basolateral and basolateral-to-apical directions. The medium pH of the cis-side was varied from 6.0 to 7.4, and the medium pH of the trans-side was kept at 7.4. In the apical-to-basolateral direction, PSal increased linearly with the calculated concentration of nonionized SAL, indicating that SAL permeability was essentially the result of nonionic diffusion. In the basolateral-to-apical direction, PSal was about 2.5-fold higher than in the apical-to-basolateral direction and was not linearly related to the concentration of nonionized SAL molecules (0-4.5 nM), suggesting that besides nonionic diffusion, SAL was transported in its ionized form by a facilitated mechanism still active at 21 degrees C. This was confirmed by measuring basolateral-to-apical fluxes at 37 degrees C and observing that probenecid, an inhibitor of organic anion secretion, and cold SAL decreased PSal. Interestingly, at 37 degrees C, PSal in the apical-to-basolateral direction was also decreased by probenecid and cold SAL, suggesting the existence of a facilitated transport in this direction. These data demonstrated that the secretory transport of SAL is present in LLC-PK1 cells. The facilitated transport observed in the apical-to-basolateral direction suggests that in proximal tubule, SAL reabsorption might occur by facilitated mechanism and nonionic diffusion.

Biological Transport↗
PubMed1992

Treatment of urinary infections in pregnancy using single versus 10-day dosing.

Pregnant patients with symptomatic and asymptomatic urinary tract infections were treated with a long and a short antibiotic regimen. Two hundred two patients were randomized prospectively to a single oral dose of 3.5 g ampicillin plus 1 g probenecid (98 patients) versus 500 mg ampicillin orally four times a day for 10 days (104 patients). The multiple-dose cure rate was statistically significantly better than that of the single-dose regimen (67.3% versus 57.1%, respectively). Interestingly, for resistant organisms, the cure rate for the long and short regimens was similar (48% versus 43%, respectively). In vitro susceptibility testing does not appear to be a good predictor of cure, at least for the single-dose group. Single-dose therapy with ampicillin and probenecid does not provide an optimal cure rate or prevent reinfection during pregnancy. Possible reasons for these findings are discussed.

Ampicillin↗
PubMed1991

Evidence for cAMP and cholate extrusion in C6 rat glioma cells by a common anion efflux pump.

C6 rat glioma cells were investigated for a shared unidirectional efflux system for cAMP and cholate. [3H]Cholate was accumulated (at pH 7.3) by scraped C6 cell monolayers via a process which was rapid initially and then slowed to a steady state after 10 min at 37 degrees C. Release of the accumulated label was also rapid (t1/2 = 2 min), was essentially complete within 15 min, and exhibited energy dependence since it could be blocked by antimycin A. Half-maximal inhibition by antimycin A occurred at 0.87 microM, and maximal inhibition exceeded 90%. Various other compounds also inhibited [3H]cholate efflux. The most effective was prostaglandin A1, which reduced efflux half-maximally at a concentration of 0.14 microM. Other inhibitors, prostaglandin B1, verapamil, probenecid, and bromosulfophathalein, produced half-maximal inhibition at 5.3, 42, 78, and 110 microM, respectively. Cholate efflux was also blocked by 40 microM vincristine. Initial influx of [3H]cholate was not affected by antimycin A, prostaglandin A1, or vincristine and hence was attributed to a process separate from efflux. C6 rat glioma cells also have the ability to produce high intracellular levels of cAMP in response to isoproterenol and to release cAMP into the medium via a carrier-mediated efflux system. When measured under the same conditions employed for cholate efflux, the efflux of cAMP was found to be sensitive to each of the inhibitors of cholate efflux. Moreover, plots of cAMP efflux versus varying concentrations of prostaglandin A1, antimycin A, prostaglandin B1, verapamil, and probenecid showed similar response curves and comparable values for half-maximal These results indicate that C6 rat glioma cells contain a unidirectional efflux pump for cholate and that this same system also appears to mediate the unidirectional efflux of cAMP. These findings support the hypothesis that various cells contain efflux pumps which exhibit a broad specificity for large organic anions of diverse structure and that the function of these efflux pumps resides primarily in cellular anion detoxification. Analogous efflux pumps for hydrophobic drugs are overproduced in tumor cells exhibiting multidrug resistance.

Animals↗
PubMed1990

Evidence in support of a chemiosmotic mechanism for stimulated prolactin release.

In order to assess the involvement of a chemiosmotic mechanism in exocytotic prolactin (PRL) release, dispersed anterior pituitary cells from female rats were used. After primary culture they were incubated in media containing bicarbonate or isethionate ions, probenecid and carbonylcyanide p-trifluoromethoxyphenyl-hydrazone (CCTP). Cells incubated without these additives or stimulated with dibutyryladenosine 3':5'-cyclic monophosphate served as controls. Further, a crude secretory granule suspension was used to study the effects of elevated osmotic pressures. The inhibition of anion transport with probenecid always significantly reduced PRL secretion, whereas bicarbonate ions had the opposite effect. The proton ionophore CCTP only inhibited stimulated release, and the substitution of chloride ions by isethionate was ineffective. Finally, it could be observed that elevated osmotic pressures reduced the lysis of isolated secretory granules when bicarbonate ions were present in the incubation medium. The results indicate that a mechanism requiring protons and bicarbonate ions is involved in stimulated PRL release and that a different mechanism, independent from proton gradients, should be considered for basal PRL secretion.

Animals↗