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PubMed1986

Leukotriene C4 transport and metabolism in the central nervous system.

The transport and metabolism of radiolabeled leukotriene (LT) C4 in the CNS were investigated after intraventricular injection. Under thiopental (Pentothal) anesthesia, New Zealand white rabbits were injected intracerebroventricularly with 0.2 ml of artificial CSF containing 2.5 microCi of [3H]LTC4 (36 Ci/mmol), 0.3 microCi of [14C]mannitol, and, in some cases, 0.9 mg of probenecid, 1.8 mg of cysteine, 1.4 micrograms of unlabeled LTC4, or 2 mg of tolazoline HCl. After 2 h, the conscious rabbits were killed, and the quantity and nature of the 3H and 14C were determined in CSF, choroid plexus, and brain. The [3H]LTC4 recovered in CSF and brain was not extensively metabolized, as greater than 70% of the 3H remained [3H]LTC4, although some spontaneous conversion to 11-trans-[3H]LTC4 occurred. Oxidized forms of [3H]LTC4, [3H]LTD4, and [3H]LTE4 did not exceed 18% in CSF and brain. After intraventricular injection of [3H]LTC4, 3H was transferred from the CSF to blood by a probenecid-sensitive, but tolazoline-insensitive, transport system in the CNS much more rapidly than mannitol. Cysteine decreased the retention of [3H]LTC4 in brain. These results are consistent with previous in vitro observations that [3H]LTC4 is transferred from CSF into blood by an efficient transport system for LTC4 in choroid plexus.

Animals↗
PubMed1986

Pantothenic acid transport through the blood-brain barrier.

The unidirectional influx of D-pantothenic acid (PA) across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique using [3H]D-PA (1.1 Ci/mmol). PA was transported across the blood-brain barrier by a saturable system that could be described by a Michaelis-Menten transport model with a half-saturation concentration and maximal influx rate of 19 microM and 0.21 nmol/g of brain/min, respectively. PA (0.3 microM) transport through the blood-brain barrier was significantly inhibited by probenecid, nonanoic acid, and biotin (all less than or equal to 0.25 mM), but not by penicillin G, pyruvate, beta-hydroxybutyrate, L-leucine (all 1 mM), or poly-L-lysine HBr (1 mg/ml). Probenecid (0.25 mM), nonanoic acid (0.5 mM), and PA (1.0 mM) did not inhibit [3H]L-leucine transport through the blood-brain barrier, whereas 30 microM-L-leucine inhibited [3H]leucine transport to 23% of control values. Thus, PA is transported through the blood-brain barrier by a low-capacity, saturable transport system with a half-saturation concentration approximately 10 times the plasma PA concentration. Although involved in the transfer of PA from blood into brain, this system does not play an important regulatory role in the synthesis of CoA from PA in brain.

Animals↗
PubMed1986

Development and characterization of pantothenic acid transport in brain.

In vitro, the transport of [3H]pantothenic acid into and from rabbit brain slices was studied. In newborn rabbits and throughout development, forebrain and cerebellar slices were able to accumulate and phosphorylate [3H]pantothenic acid comparably to slices from adults. The accumulation and phosphorylation of [3H]pantothenic acid by adult forebrain slices were not decreased by substitution of LiCl for NaCl in the artificial CSF or by addition of short-chain fuels (e.g., 5 mM pyruvate or acetoacetate) to the medium. However, probenecid and ouabain (both 1 mM) and medium-chain fatty acids (e.g., 0.1 mM octanoate, nonanoate, and decanoate) profoundly inhibited [3H]pantothenic acid accumulation by forebrain slices but not intracellular phosphorylation and conversion to [3H]CoA. There in vitro results suggest that brain slices accumulate pantothenic acid by a saturable system (probably facilitated diffusion) that is sensitive to inhibition by probenecid and medium-chain fatty acids.

Animals↗
PubMed1988

Fatty acid transport through the blood-brain barrier.

Across the cerebral capillaries, the anatomical locus of the blood-brain barrier, the unidirectional influxes of the saturated fatty acids, octanoic and myristic acids, and the unsaturated essential fatty acid, linoleic acid, were measured. Employing an in situ rat brain perfusion technique that allows control of perfusate composition and accurate measurement of perfusate-to-brain fatty acid transport, we found that both [14C]octanoic and [14C]myristic acids were transported through the blood-brain barrier in vivo, in large part, by a specific, probenecid-sensitive transport system. However, the transport of [14C]linoleic acid was not probenecid sensitive. With 0.5 microM fatty acid but no plasma proteins in the perfusate, the permeability-surface area constant was higher for myristic acid (4.8 X 10(-2) X s-1) than for octanoic and linoleic acids (1.5 and 1.2 X 10(-2) X s-1, respectively). Approximately 70, 30, and 25% of the [14C]myristic, [14C]octanoic, or [14C]linoleic acids, respectively, were extracted from the perfusate.

Animals↗
PubMed1970

Some factors influencing the release of 5-hydroxyindol-3-ylacetic acid in the forebrain.

1. Electrical stimulation of the mid-brain raphé in anaesthetized adrenalectomized rats produced a significant decrease in the forebrain content of 5-hydroxytryptamine (5-HT) and an increase in the concentration of 5-hydroxyindol-3-ylacetic acid (5-HIAA).2. Stimulation of peripheral sensory nerves did not influence either the forebrain content of 5-HIAA or the efflux of 5-HIAA from the cerebral cortex.3. Probenecid (200 mg/kg) caused a twofold increase in 5-HIAA content of the rat's forebrain, while the efflux of 5-HIAA from the cerebral cortex remained unchanged.4. Stimulation of the mid-brain raphé in animals pretreated with probenecid does not produce the rise in the forebrain levels of 5-HIAA seen in stimulated untreated controls and does not affect the efflux of 5-HIAA from the cerebral cortex.5. In preliminary experiments, lysergic acid diethylamide (LSD 25) substantially reduced and/or prevented the increase in the release of 5-HIAA in the forebrain observed in untreated animals with raphé stimulation.

Adrenalectomy↗
PubMed1977

Neurotransmitter precursor amino acids in the treatment of multi-infarct dementia and Alzheimer's disease.

Ten patients with severe dementia due to Alzheimer's disease (AD) or multi-infarct dementia (MID) or both, were treated with the precursor amino acids of the neurotransmitters serotonin and dopamine. The precursor amino acids (PAA) were given orally in a preparation that included tyrosine (4 gm daily) and 5-hydroxy-tryptophan (5-HTP) (800 mg daily), plus carbidopa (100 mg daily) as an aromatic amino-acid decarboxylase inhibitor. Diagnosis was established by an electroencephalogram, brain scan, computerized axial tomographic scan, and in one case by necropsy findings. Serial clinical evaluations and measurements of neuropsychologic function were performed. Levels of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) were determined before and after administration of probenecid. Side effects of the PAA therapy were diarrhea, drowsiness, nausea, vomiting and agitation, all of which were controlled by reducing the dosage. One patient with MID and one with AD+MID showed clinical and psychologic improvement, but the others did not improve. Analysis of the cerebrospinal fluid for HVA and 5-HIAA before and after the probenecid test indicated some improvement in the metabolic turnover of these acid metabolites of serotonin and dopamine after administration of their precursor amino acids.

5-Hydroxytryptophan↗
PubMed1987

Transport of p-aminohippuric acid (3H-PAH), inulin and dextran out of the cranial cavity: a methodological study using intraventricular injection and sample combustion.

Material injected into the cerebral ventricles can leave the cerebrospinal fluid (CSF) but remain in the cranial cavity. To analyze the disappearance of 3H- and of 14C-labelled material from the cranial cavity, such material was injected into the lateral ventricles together with a bulk flow marker, labelled with the other radionuclide. In the present pilot study 3H-PAH and 14C-inulin were used. Five microliter of a mixture was injected into each lateral cerebral ventricles in rats, which were killed at various intervals. The whole skull was analyzed without opening the CSF space after homogenization in the deep-frozen state. The samples were combusted and analyzed by liquid scintillation counting. Probenecid, injected intraperitoneally, inhibited the removal of 3H-PAH from the skull cavity, as anticipated. Immediately after the intraventricular injection, however, 3H-PAH was transiently retained, probably by uptake into actively transporting tissue. After injection of probenecid, this delay in removal was reduced. The difference in disappearance rate between 3H-PAH and 14C-inulin was estimated by comparing the 3H/14C ratio in the skulls with that in the injected solution, which appeared to be a better method than comparing the recovery of each compound.

Aminohippuric Acids↗
PubMed1991

Characteristics of ascorbic acid uptake by isolated ox neurohypophyseal nerve terminals and the influence of glucocorticoid and tri-iodothyronine on uptake.

Isolated nerve endings (neurosecretosomes) from ox neurohypophyses took up L-[14C]ascorbic acid by a process or processes which showed energy dependence and which could be inhibited by unlabelled ascorbic acid in micromolar concentrations and by isoascorbic acid in millimolar concentrations, whereas dehydroascorbic acid only inhibited in concentrations of about 100 mM. The uptake showed saturation with increasing concentration of ascorbic acid and a Km value of 97 microM. Uptake was inhibited by increasing glucose concentration in the medium or by adding cytochalasin B, phloridzin, ethanol or probenecid to the medium. The uptake was inhibited by lowering the sodium concentration and by lack of calcium. These facts suggest the presence of both a glucose-dependent uptake and a sodium-dependent uptake. Cortisol and tri-iodothyronine inhibited uptake. This effect of cortisol, but not of tri-iodothyronine, was dependent on the presence of sodium in the medium. For both hormones it was still present when phloridzin or probenecid was added to the medium.

Animals↗
PubMed1996

In-vivo clearance study of vancomycin in rats.

The renal handling of vancomycin in rats and the effects of various drugs (probenecid, cimetidine and quinidine) on urinary excretion of the antibiotic were investigated by in-vivo clearance. The vancomycin-to-inulin excretion ratio (ER) was greater than unity at various infusion rates of vancomycin. Quinidine, co-administered with vancomycin, significantly decreased the total, renal and net secretory clearance of the antibiotic. Cimetidine also decreased, though not significantly, the secretory clearance of vancomycin by about 20%, but probenecid did not. These results suggested that vancomycin is secreted in renal tubules in rats, and that quinidine decreases the total clearance of vancomycin partly by inhibiting its tubular secretion in the kidney.

Analysis of Variance↗
PubMed1978

Renal handling of phenol red. III. Bidirectional transport.

1. The renal excretion of phenol red and other phenolsulphophthalein dyes (bromophenol blue and bromothymol blue) was studied in clearance experiments on anaesthetized rabbits. 2. Net tubular excretion of phenol red reached a maximal value of 8 mumole/min at a plasma concentration of ultrafiltrable dye of about 0.1 mM and was decreased at higher plasma concentrations. Decreases in net tubular excretion at high plasma concentrations were also obtained for bromophenol blue and bromothymol blue suggesting tubular reabsorption in addition to tubular secretion of the dye. Conclusive evidence for reabsorption was provided by administration of probenecid which caused a fall in the excretion of the dyes below that filtered by the glomeruli. 3. Tubular reabsorption of phenol red during probenecid administration appeared to be proportional to the glomerular load and was increased under experimental conditions leading to a decrease of urinary pH. Experiments involving efflux of phenol red from liposomes gave no evidence of a significant role of transmembrane passage by non-ionic diffusion. It is suggested that the pH dependence of the reabsorptive process is the result of preferential reabsorption of the acid as compared to the basic form of the indicator dye across a hydrophilic pathway in the transporting membranes. 4. Clearance ratio of phenol red to that of p-aminohippurate at low plasma concentrations was about 0.3. They low degree of extraction of phenol red from renal plasma is attributed both to tubular reabsorption and binding of the dye by plasma proteins.

Absorption↗
PubMed2004

Hepatobiliary excretion of berberine.

Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with high-performance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg(-1) significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

Human organic anion transporters and human organic cation transporters mediate renal antiviral transport.

Renal excretion is an important elimination pathway for antiviral agents, such as acyclovir (ACV), ganciclovir (GCV), and zidovudine (AZT). The purpose of this study was to elucidate the molecular mechanisms of renal ACV, GCV, and AZT transport using cells stably expressing human organic anion transporter 1 (hOAT1), hOAT2, hOAT3, and hOAT4, and human organic cation transporter 1 (hOCT1) and hOCT2. Time- and concentration-dependent uptake of ACV and GCV was observed in hOAT1- and hOCT1-expressing cells. In contrast, uptake of valacyclovir, L-valyl ester of ACV, was observed only in hOAT3-expressing cells. On the other hand, AZT uptake was observed in hOAT1-, hOAT2-, hOAT3-, and hOAT4-expressing cells. The Km values of ACV uptake by hOAT1 and hOCT1 were 342.3 and 151.2 microM, respectively, whereas those of GCV uptake by hOAT1 and hOCT1 were 895.5 and 516.2 microM, respectively. On the other hand, the Km values of AZT uptake by hOAT1, hOAT2, hOAT3, and hOAT4 were 45.9, 26.8, 145.1, and 151.8 microM, respectively. In addition, probenecid weakly inhibited the hOAT1-mediated ACV uptake. In conclusion, these results suggest that hOAT1 and hOCT1 mediate renal ACV and GCV transport, whereas hOAT1, hOAT2, hOAT3, and hOAT4 mediate renal AZT transport. In addition, L-valyl ester appears to be important in differential substrate recognition between hOAT1 and hOAT3. hOAT1 may not be the molecule responsible for the drug interaction between ACV and probenecid.

Acyclovir↗
PubMed1978

Piperacillin: human pharmacokinetics after intravenous and intramuscular administration.

The pharmacokinetics of piperacillin were studied in a total of 26 Caucasian normal male volunteers. Single intramuscular doses of 0.5, 1.0, and 2.0 g were given to three groups, each containing eight volunteers. Mean peak serum concentrations of 4.9, 13.3, and 30.2 mug/ml were assayed at 30 to 50 min, and measurable levels were present up to 4, 6, and 8 h, respectively, after dosing. Single intravenous bolus doses of 1.0, 2.0, 4.0, and 6.0 g were given to four groups of five subjects, and mean serum concentrations of 70.7, 199.5, 330.7, and 451.8 mug/ml were measured at the end of the injections. The antibiotic had a mean terminal serum half-life of 60 to 80 min after the intramuscular doses and 36 to 63 min after intravenous administrations, depending on the dose. The apparent distribution volume was 20 to 24 liters/1.73 m(2), and distribution volume at steady state was 16 to 19 liters/1.73 m(2). Mean urinary recovery in 24 h was 74 to 89% for the intravenous doses and 57 to 59% for the intramuscular doses. The piperacillin-creatinine clearance ratios indicated that the proportion of renal excretion of piperacillin through tubular secretion was 56 to 73%, and this was confirmed by the renal clearance data from eight volunteers receiving probenecid treatment before the piperacillin dose. Probenecid (1 g given orally before administration of piperacillin) increased peak serum concentration by 30%, terminal serum half-life by 30%, and the area under the plasma concentration curve by 60%, and it decreased the apparent distribution volume by 20% and the renal clearance of the intramuscularly administered (1 g) antibiotic by 40%. Injections of piperacillin by both parenteral routes were well tolerated.

Administration, Oral↗
PubMed1980

Cefoxitin concentrations in the cerebrospinal fluids of patients with meningitis.

The concentrations of cefoxitin in serum and cerebrospinal fluid (CSF) were measured simultaneously in three groups of patients, 12 with aseptic meningitis (group 1) and 17 and 14 with bacterial meningitis (groups 2 and 3). The patients in group 1 received a single intravenous dose of 2 g of cefoxitin without other antimicrobial therapy. In addition to conventional doses of ampicillin or benzyl penicillin, patients in groups 2 and 3 received repeated infusions of 2 g of cefoxitin every 4 h for the first 3 or 4 days of the study and again on day 10. Additionally, group 3 received probenecid in a loading dose of 1 g followed by 0.5 g every 6 or 8 h. Concentrations of cefoxitin in CSF and serum were determined 1 or 2 h after infusion in group 2 and 2 h after infusion in group 3. The concentrations of cefoxitin in CSF did not reach detectable levels (1.56 microgram/ml) in 11 of the 12 patients in group 1. A level of 2.8 microgram of cefoxitin per ml of CSF was found, with an accompanying level of 30 microgram/ml of serum, in patient 12. In the group 2 patients with bacterial meningitis, the mean CSF concentrations were 3.3, 4.7, and 2.9 microgram/ ml on days 1, 3, and 10 of treatment, with simultaneous serum levels of 8, 9, and 8 microgram/ml. At similar times periods, the mean levels of cefoxitin in group 3 patients (with concomitant probenecid) were 8.6, 12.3, and 4.3 microgram/ml of CSF and 57, 35, 27 microgram/ml of serum.

Adolescent↗
PubMed1983

Mechanism of renal excretion of AM-715, a new quinolonecarboxylic acid derivative, in rabbits, dogs, and humans.

The mechanisms of the renal excretion of AM-715, a synthetic antimicrobial agent, were studied in rabbits, dogs, and humans. In both rabbits and humans, AM-715 clearance was greater than creatinine clearance and was profoundly decreased by the administration of probenecid. Thus, in these subjects, AM 715 was cleared by both tubular secretion and glomerular filtration. In dogs, however, the excretion ratio (close to unity), biological half-life, and stop-flow pattern of AM-715 were not affected by probenecid, indicating that the renal excretion of AM-715 took place mostly through glomerular filtration. These results suggest that renal excretion of AM-715 differs with animal species.

Adult↗
PubMed1983

Renal disposition of moxalactam in experimental animals as revealed by stop-flow analysis.

The mechanisms of moxalactam excretion were studied by stop-flow analysis in dogs, monkeys, and rabbits. In dogs, the amount of moxalactam excreted in the urine was almost equal to that estimated by glomerular filtration. There was no specific moxalactam peak corresponding to the p-aminohippuric acid (PAH) peak in the stop-flow patterns of the dogs. The PAH peak disappeared with administration of probenecid, but the moxalactam stop-flow pattern showed no change. In monkeys, no specific moxalactam peak corresponding to the PAH peak could be detected. In the stop-flow pattern of the rabbit, the peak moxalactam concentration corresponded with that of PAH and disappeared with probenecid. These results suggest that in dogs and monkeys renal excretion of moxalactam takes place mostly through glomerular filtration. In rabbits, however, there is a small renal tubular secretory component added to the primary element, glomerular filtration. These observations point to differences in the mechanisms of moxalactam excretion in different animal species.

Animals↗
PubMed1986

Cefuroxime axetil for treatment of uncomplicated gonorrhea.

Oral cefuroxime axetil (1 g) plus probenecid cured 29 of 30 urethral and 6 of 6 rectal gonococcal infections in men; alone the drug cured 22 of 23 urethral and 4 of 6 rectal infections. No toxicity was observed. Cefuroxime axetil alone is effective for urethral gonorrhea in males; rectal gonorrhea probably requires additional probenecid.

Adolescent↗
PubMed1987

Single- and multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans.

Fleroxacin (Ro 23-6240; AM-833) is a new trifluorinated quinolone exhibiting high activity against a broad spectrum of gram-negative and gram-positive bacteria. Healthy male volunteers received, according to a randomized scheme, oral doses of 200, 400, or 800 mg of fleroxacin in tablet form, an intravenous infusion of 100 mg, or 400 mg of fleroxacin orally together with 1,000 mg of probenecid. Fleroxacin is characterized pharmacokinetically by a long elimination half-life (9 to 10 h) and high concentrations in plasma (e.g., maximum concentration of 2.3 micrograms/ml after an oral dose of 200 mg). The volume of distribution clearly exceeds 1 liter/kg and suggests a good tissue penetration. Within 60 h, the cumulative urinary recovery of unchanged drug amounted to 50 to 60% of the dose. The renal clearance of unbound drug was 137 ml/min, and probenecid had no significant effect on renal elimination. A good linear correlation (r = 0.999) was found between doses from 100 to 800 mg and the resulting values of area under the concentration-time curve. The absolute bioavailability of the administered tablet was practically 100%. During oral multiple dosing of 800 or 1,200 mg of fleroxacin once a day over 10 consecutive days, the accumulation of the drug in plasma was close to the theoretically predicted value of 1.3 and reflected the persistence of linear pharmacokinetics.

Administration, Oral↗