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PubMed1977

The dynamics of dopamine metabolism in various regions of rat brain.

Dopamine metabolism was studied in various regions of rat brain by following the decline of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) from brain after treatment with pargyline, or from the accumulation of the acids after treatment with probenecid. The decline of DOPAC and HVA after pargyline treatment appeared exponential in all regions of brain studied with half-lives of about 13 min for HVA and 6.5 min for DOPAC. DOPAC was the major metabolite of dopamine, with various brain regions producing between 2-5 times more DOPAC than HVA. HVA accumulated after treatment with probenecid but the accumulation in 1 h did ot account for all of the HVA apparently eliminated from brain. DOPAC accumulated in some regions of brain (medulla, hypothalamus and midbrain) and not in others (cerebellum, cortex, striatum and hippocampus) after probenecid treatment. We conclude that dopamine metabolism is not uniform in brain and that the accumulation of DOPAC and HVA in brain after probenecid treatment only accounts for a minor fraction of the dopamine formed in brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Mechanisms for tolerance to methamphetamine effects.

Pretreatment with incremental increases in methamphetamine causes tolerance to serotonergic effects caused by challenging with multiple high doses of methamphetamine (11.5 mg/kg/dose). The brain concentration of methamphetamine following this challenge was reduced in tolerant rats, yet the plasma concentration was elevated. The tolerance was selective for methamphetamine and did not occur when cocaine was used in the pretreatment. The possibility that tolerance affects the distribution of methamphetamine in or out of the brain through an active transport system was examined by combining the transport-blocking drug, probenecid, with a low dose of methamphetamine. The presence of probenecid enhanced methamphetamine-induced serotonergic changes in the hippocampus. The brain concentration of methamphetamine increased in the presence of probenecid; however, a similar increase in the plasma methamphetamine concentration suggests that the effects of probenecid on methamphetamine distribution are not related to the redistribution of methamphetamine that occurs in tolerant animals.

Animals↗
PubMed2006

Tubular transporters and clearance of adefovir.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR-) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03+/-0.02l/h) than in normal control (0.09+/-0.05l/h), in normal probenecid (0.10+/-0.07l/h) and in TR- control rats (0.13+/-0.07l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

ATP-Binding Cassette Transporters↗
PubMed2005

[Tubular transporters OAT1 and MRP2 and clearance of adefovir].

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

Adenine↗
PubMed1980

Cefoxitin levels in human aqueous humor.

We administered 2 g of cefoxitin to 25 patients before cataract surgery. An additional 23 patients received 500 mg of probenecid 30 minutes before the 2-g doses of cefoxitin. Average aqueous humor levels of 1.54, 3.16, 2.46, 1.22, and 0.82 microgram/ml were achieved at 30 minutes and one, two, four, and six hours, respectively, after the 2-g dose. The addition of probenecid prolonged significant aqueous humor levels. Therapeutic levels against common gram-positive pathogens were consistently achieved at two hours after injection without probenecid and from two to four hours after injection with probenecid. Therapeutic levels effective against Enterobacteriaceae were inconsistent.

Aqueous Humor↗
PubMed1998

Control of renal factors in plasma homovanillic acid measurements.

To identify and control renal factors affecting plasma homovanillic acid (HVA), a dopamine metabolite and an indicator of brain dopamine activity in clinical research, nine healthy subjects were studied on 5 nonconsecutive days. First study day was the baseline and on the other days base, salt, water, or probenecid loads were given. On each day serial concentrations of HVA and serotonin metabolite 5-hyroxyindoleacetic acid (HIAA), another organic anion, in plasma were measured. Results suggested that base, salt, and water loads did not affect plasma concentrations of either metabolite. Probenecid, which partially blocks renal organic anion transport, induced similar increases in plasma HVA and HIAA. When plasma HVA:HIAA ratio was used to control for the effect of probenecid, differences between baseline and probenecid days were no longer significant. Results suggest that HVA and HIAA are similarly handled by the kidney and that simultaneously measured plasma HIAA could be used to distinguish renal influences in plasma HVA studies.

Adult↗
PubMed1977

Cyclic AMP in cerebrospinal fluid of manic and depressive patients.

Cyclic 3',5'-adenosine monophosphate (c-AMP) was measured in cerebrospinal fluid (CSF) of manic and depressive patients with and without probenecid administration both before and during treatment with various psychotropic drugs. Oral probenecid (100 mg/kg) produced substantial c-AMP accumulations in CSF suggesting a probenecid-sensitive transport mechanism for c-AMP. Baseline and probenecid-induced accumulations of c-AMP were not significantly different in manic and depressed patients, while baseline levels in depressed patients were higher than those in neurological controls. Imipramine, amitriptyline, lithium, tryptophan, and electroconvulsant therapies did not significantly alter levels or accumulations of c-AMP in CSF of depressed patients.

Administration, Oral↗
PubMed1994

In vitro and in vivo transport of zidovudine (AZT) across the blood-brain barrier and the effect of transport inhibitors.

The transport of the antiviral nucleoside analogue zidovudine (3'-azido-3'-deoxythymidine; AZT) into the central nervous system (CNS) was characterized in vitro and in vivo. The in vitro model consisted of primary cultures of isolated bovine capillary endothelial cells. The transport rate of AZT across the monolayer, expressed as endothelial permeability P, was determined following luminal and abluminal administration. P did not differ between the two administration sites (luminal, 1.65 +/- 0.44 cm/min/10(3); abluminal, 1.63 +/- 0.28 cm/min/10(3)). The transport of AZT across the endothelial cell monolayer was found to be concentration independent in the range between 0.4 and 50 micrograms/mL. AZT transport was not affected by pretreatment of the cells with either metabolic inhibitors (DODG and DODG/NaN3) or probenecid. This suggests that AZT passes the monolayer mainly by passive diffusion. The in vivo transport of AZT across the blood-brain barrier and the blood-CSF barrier was studied in male Wistar rats after coadministration of potential inhibitors of active transport of AZT: probenecid (organic anion transport) and thymidine (nucleoside transport). Intracerebroventricular and intravenous coadministration of probenecid caused a significant (P < 0.001) increase in the CSF/plasma concentration ratio compared to the control phase, indicating that the organic anion carrier is involved in AZT transport from CSF to blood. Since there was no effect of probenecid on the transport of AZT in vitro, it is suggested that this carrier is located at the choroid plexus. Coadministration of thymidine did not affect the CSF/plasma concentration ratio, suggesting that a nucleoside carrier system is not involved in AZT transport into or out of the CNS.

Analysis of Variance↗
PubMed1998

A possible role of multidrug resistance-associated protein (MRP) in basic fibroblast growth factor secretion by AIDS-associated Kaposi's sarcoma cells: a survival molecule?

Kaposi's sarcoma (KS) is considered a disorder of cytokines. Basic fibroblast growth factor (bFGF) is produced by AIDS-associated KS (AIDS-KS) cells and supports their growth in an autocrine and paracrine manner. bFGF lacks a signal sequence; therefore, its mechanism of secretion is unclear. In this study, we investigate the role of two important members of ATP-binding cassette transport proteins, the P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), in the secretion of bFGF from AIDS-KS cells. Expression of P-gp and MRP was examined at both the protein and the mRNA levels by flow cytometry and RT-PCR respectively. Intracellular and secreted bFGF was measured by ELISA. AIDS-KS cells expressed MRP at both the mRNA and the protein levels; however, no P-gp expression was detected at either the mRNA or the protein level. Probenecid, a putative inhibitor of MRP efflux function, in a concentration-dependent manner, inhibited bFGF secretion, with a concomitant increase in intracellular bFGF, demonstrating that probenecid blocks bFGF secretion without inhibiting its synthesis. In addition, probenecid induced apoptosis in AIDS-KS cells. AIDS-KS cells expressed fas, bcl-2, and bcl-xL genes but lacked fasL and bax gene expression. These data suggest that bFGF is secreted from AIDS-KS cells via a probencid-sensitive transporter, most likely in MRP. Furthermore, probenecid appears to induce apoptosis in AIDS-KS cells by depriving them of the growth promoting activity of bFGF. These data suggest that MRP may play a role as a survival molecule in AIDS-KS cells.

AIDS-Related Opportunistic Infections↗
PubMed1981

Kinetics and renal handling of cefonicid.

Cefonicid kinetics were determined after intravenous and intramuscular injection and the renal handling of the drug was examined, including the effect of probenecid on its excretion. Peak serum levels after 1000 and 500 mg intravenously was 221 and 91 micrograms/ml. The half-life (t1/2) was the same for both regimens (3.5 hr). Intramuscular injection of the 1000- and 500-mg doses resulted in peak serum levels of 112 and 40 micrograms/ml. When probenecid was given with the 500-mg dose, the peak serum level was 61 micrograms/ml and the time to peak level rose from 1.3 to 2.5 hr. The t1/2 after 1000 and 500 mg alone was much the same at 4.8 and 4.9 hr. The addition of probenecid to the 500-mg dose extended the t1/2 and 7.5 hr. Renal clearance, excretion, and secretion rates for cefonicid were reduced by the addition of probenecid. Cefonicid's long t1/2 and high blood levels may provide clinical efficacy with a single daily dose.

Adult↗
PubMed1992

Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats.

Kynurenic acid is the only known endogenous excitatory amino acid receptor antagonist in the central nervous system. In the present study, we examined whether increasing brain concentrations of kynurenic acid by loading with its precursor L-kynurenine, or blocking its excretion with probenecid, could exert neuroprotective effects. Neuroprotective effects were examined in a neonatal model of hypoxia-ischemia, and following intrastriatal injection of N-methyl-D-aspartate (NMDA). Seven-day-old rats underwent unilateral ligation of the carotid artery, followed by exposure to 8% oxygen for 1.5 h. L-kynurenine administered 1 h before the hypoxia-ischemia showed a dose-dependent significant neuroprotective effect, with complete protection at a dose of 300 mg kg-1. The induction of c-fos immunoreactivity in cerebral cortex was also blocked by this dose of L-kynurenine. Probenecid alone had moderate neuroprotective effects, while a combination of a low dose of probenecid with doses of 50-200 mg kg-1 of L-kynurenine showed significant dose-dependent neuroprotection. Kynurenine dose-dependently protected against NMDA neurotoxicity in 7-day-old rats. Neurochemical analysis confirmed that L-kynurenine with or without probenecid markedly increased concentrations of kynurenic acid in cerebral cortex of 7-day-old rats. These results show for the first time that pharmacologic manipulation of endogenous concentrations of kynurenic acid can exert neuroprotective effects.

Animals↗
PubMed1982

The time course of delivery of furosemide into urine: an independent determinant of overall response.

After an oral or intravenous dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On average, approximately half as much reaches the intraluminal site of action with an oral compared to an intravenous dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose, or after pretreatment with probenecid, amounts of drug are for longer periods of time at the "steep" portion of the dose-response curve. Our analysis shows this not to be the case. For furosemide, the "slope factor" of the dose-response curve is such that the amount of diuretic delivered into the urine which is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does intravenous administration. By so doing, total response to an oral dose approaches that of intravenous dosing despite delivering half the amount of drug to the active site, and after probenecid an intravenous dose causes a greater response than intravenous dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.

Administration, Oral↗
PubMed1980

Estimation of monoamine and cyclic-AMP turnover and amino acid concentrations of spinal fluid in autistic children.

A group of autistic children had the concentrations of spinal fluid 5-HIAA, HVA and cAMP studied before and twenty-four hours after afflux blockade with probenecid. Spinal fluid aminoacids were studied before probenecid administration and found to be normal. Three children lacked an increase in the concentration of 5-HIAA after probenecid administration, and two had only modest increases in the concentration of spinal fluid HVA. The concentration of spinal fluid cAMP was increased by probenecid administration in all eight children. These findings suggest an abnormality in monoamine metabolism in a small group of autistic children.

Amines↗
PubMed1983

Rat brain norepinephrine metabolism: substantial clearance through 3,4-dihydroxyphenylethyleneglycol formation.

To assess whether the metabolic clearance of rat brain norepinephrine (NE) through 3,4-dihydroxyphenylethyleneglycol (DHPG) formation is quantitatively comparable or greater than through 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) production, we studied the accumulation rates of conjugated DHPG and MHPG following probenecid administration in whole brain as well as in several brain regions. Administration of increasing doses of probenecid (100-500 mg/kg, i.p.) 1.5 h before sacrifice produced a dose-dependent increase of conjugated DHPG and MHPG levels. The maximum increment of these conjugated metabolites occurred at a dose of 300 mg/kg or higher. During the first hour following probenecid administration (300 mg/kg, i.p.), rat brain conjugated DHPG and MHPG levels accumulated linearly at a rate of 646 and 319 pmol/g/h, respectively. With the probenecid technique, the estimated appearance rates of conjugated DHPG significantly exceeded those of conjugated MHPG in hypothalamus, midbrain, brainstem, hippocampus, and cerebral cortex. These results clearly indicate that under resting conditions, formation and efflux of conjugated DHPG is the major route of metabolic clearance of rat brain NE.

Animals↗
PubMed1984

Concurrent determination of brain dopamine and 5-hydroxytryptamine turnovers in individual freely moving rats using repeated sampling of cerebrospinal fluid.

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters.

A clinical drug-drug interaction between famotidine (a H2 receptor antagonist) and probenecid has not been reproduced in rats. The present study hypothesized that the species-dependent probenecid sensitivity is due to a species difference in the contribution of renal organic anion and cation transporters. The transport activities of the H2 receptor antagonists (cimetidine, famotidine, and ranitidine) by rat and human basolateral organic anion and cation transporters [human organic anion transporter (hOAT) 1, hOAT2, r/hOAT3, rat organic cation transporter (rOct) 1, and r/hOCT2] were compared using their cDNA transfectants. The transport activities (Vmax/Km) of famotidine (Km, 345 microM) by rOat3 were 8- and 15-fold lower than those of cimetidine (Km, 91 microM) and ranitidine (Km, 155 microM), respectively, whereas the activity by hOAT3 (Km, 124 microM) was 3-fold lower than that of cimetidine (Km, 149 microM) but similar to that of ranitidine (Km, 234 microM). Comparison of the relative transport activity with regard to that of cimetidine suggests that famotidine was more efficiently transported by hOAT3 than rOat3, and vice versa, for ranitidine. Only ranitidine was efficiently transported by hOAT2 (Km, 396 microM). rOct1 accepts all of the H2 receptor antagonists with a similar activity, whereas the transport activities of ranitidine and famotidine (Km, 61/56 microM) by r/hOCT2 were markedly lower than that of cimetidine (Km, 69/73 microM). Probenecid was a potent inhibitor of r/OAT3 (Ki, 2.6-5.8 microM), whereas it did not interact with OCTs. These results suggest that, in addition to the absence of OCT1 in human kidney, a species difference in the transport activity by hOAT3 and rOat3 accounts, at least in part, for the species difference in the drug-drug interaction between famotidine and probenecid.

Animals↗
PubMed1983

Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans.

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of N-formimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of N-formimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH.

Adult↗
PubMed1977

A double trial of amoxycillin in the treatment of gonorrhoea.

A double blind comparison of two regimens of amoxycillin plus probenecid in the treatment of uncomplicated anogenital gonorrhoea is reported. Forty-three (86-0%) of 50 patients treated with 1 g amoxycillin plus 1 g probenecid and followed-up for 14 days were regarded as cured, and 51 (94-4%) of 54 patients treated with 3 g amoxycillin plus 1 g probenecid were regarded as cured. Fifty-nine per cent of 69 isolates of Neisseria gonorrhoeae were sensitive to amoxycillin (minimum inhibitory concentration less than or equal to 0-05 mg/ml). Although there was no statistical difference between the results of the two regimens it is concluded that the larger dose of amoxycillin plus probenecid is required where only 60% of gonococci are sensitive to amoxycillin.

Amoxicillin↗