The effect of probenecid on the pharmacokinetics and distribution of cefoxitin in healthy volunteers.

1 Cefoxitin was given by acute intravenous injection to six healthy volunteers, in a crossover study to investigate the effects of concurrent probenecid administration. 2 Serum antibiotic concentrations were determined by microbiological assay. Cefoxitin concentrations were simultaneously determined in the fluid of blisters produced by topical cantharides. All antibiotic was accounted for in the urine. 3 Cefoxitin was administered by intravenous infusion, subsequent to a loading dose, to produce steady state levels in the region of 10 microgram/ml, in one volunteer. The procedure was later repeated after prior administration of probenecid in the same subject. 4 Pharmacokinetic analyses indicated significant changes only in the parameters associated with renal excretion of drugs. Clearance was reduced by half. 5 The absolute and relative amounts of antibiotic in the central and peripheral compartments were calculated for both modes of administration. In the acute study probenecid produced a small change in distribution away from the peripheral or tissue compartment, towards the central compartment. 6 There was no elevation of initial serum concentrations and sustained levels of antibiotic could be accounted for principally by retarded excretion produced by probenecid, with little contribution by alteration in the disposition of antibiotic. 7 The sustained serum levels of cefoxitin that resulted from its decreased excretion were also reflected in blister fluid. It was concluded that the sustained cefoxitin levels produced by probenecid resulted in similar raised levels in the peripheral or "tissue' compartment, since the redistribution away from the peripheral compartment did not contribute materially to other changes in disposition of drug.     

Pharmacokinetics of ticarcillin in man

Summary The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [³⁵S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.     

Pharmacokinetics of cephradine given intravenously with and without probenecid.

1 In the light of questions raised by an earlier oral study (Welling, Dean, Selen, Kendall & Wise, 1979) the influence of probenecid on the pharmacokinetics of intravenously administered cephradine has been investigated. 2 Intravenous administration of cephradine resulted in a bi-exponential curve and the level of antibiotic after 15 min was significantly greater when subjects received probenecid than when they did not. The influence of probenecid on urinary excretion of cephradine was similar to that observed previously. 3 The increase in serum of cephradine due to probenecid could be accounted for by the decrease in the elimination rate of the antibiotic. These results are discussed in the light of other observations.     

The influence of co-administered organic acids on the kinetics and dynamics of frusemide.

1. This study examines the effects of pretreatment with probenecid with and without pyrazinamide on the elimination kinetics and diuretic action of frusemide. 2. Six normal male volunteers received 40 mg frusemide i.v. on three occasions; i.e. once on its own and twice after pretreatment with 2 g probenecid with and without 3 g pyrazinamide. Both these latter drugs were administered orally 3 h before frusemide administration thereby attempting optimal suppression of proximal tubular secretion. Urinary losses were replaced i.v. with isovolumetric amounts of normal saline while insensible losses were compensated for by taking tap water orally. 3. The mean cumulative urinary frusemide excretion was significantly and similarly decreased by pretreatment with probenecid (34.9%) and probenecid plus pyrazinamide (33.6%), but the mean total volume of diuresis and the mean cumulative urinary sodium excretion did not differ significantly between treatments over the 5 h period. 4. The diuretic efficiency of frusemide was significantly increased with probenecid pretreatment during the first 90 min period after frusemide administration. Furthermore, in the first 30 min after administration the percent sodium fractional excretion was higher after pretreatment with probenecid even though the mean frusemide excretion rate was more than three times with frusemide alone than with probenecid-frusemide (374.4 micrograms min-1 vs 119.1 micrograms min-1). Pretreatment with probenecid results in a higher concentration on the peritubular or blood side of the tubules and these results lead us to question the unconditional acceptance of a luminal site of action for the loop diuretics. Alternatively, probenecid may act in some other way to increase the effects of frusemide.     

The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion.

1. The renal tubular excretion of cefuroxime and ceftazidime in relation to the coadministration of probenecid was investigated in eight and two healthy subjects, respectively. 2. Cefuroxime or ceftazidime were administered by i.v. infusion and 1 g probenecid was administered orally after steady state plasma concentrations of the cephalosporin were reached. 3. In a second session the same antibiotic was administered at increasing infusion rates such that three different levels of plasma drug concentration were achieved. 4. The renal clearance of antibiotic was calculated based upon unbound plasma concentration, and tubular clearance was estimated by subtracting inulin clearance from the renal clearance of the antibiotic. 5. Non-linear regression analysis was used to estimate parameters describing the saturability of tubular excretion and the effect of probenecid inhibition, i.e. EC50 and Rtub,max, could be established for cefuroxime: EC50 was 248 (s.d. 130) mg l-1 and Rtub,max was 1.852 (s.d. 0.577) mg h-1. Tubular excretion of ceftazidime was practically zero. The EC50 of probenecid for inhibition of the tubular excretion of cefuroxime was 0.80 (s.d. 0.31) mg l-1. 6. The results indicate that in the therapeutic plasma concentration range of cefuroxime its renal clearance is not saturated. Probenecid at therapeutic doses will block tubular excretion of cefuroxime almost completely.     

药物代谢动力学研究(Ⅰ)——硫脒头孢菌素

本文对硫脒头孢菌素在7例健康受试者体内的药物代谢动力学过程,以及合用丙磺舒的影响,进行了初步的分析。静脉注射后的血药浓度-时间曲线符合开放型二室模型;但肌内注射时可以简化为开放型单室模型。合用丙磺舒对硫脒头孢菌素药代动力学过程的影响比较复杂。对计算的主要结果进行分析讨论后认为:丙磺舒能够抑制硫脒头孢菌素的经尿排泄,表现在尿药排泄量减少,血药峰浓度及血药浓度-时间曲线下总面积增加。对合用丙磺舒的临床意义也进行了讨论。与常用头孢菌素的药代动力学特性,进行了讨论比较。     

The effect of probenecid on the renal tubular excretion of benzylpenicillin.

1 The aim of this study was to establish whether the renal tubular excretion of benzylpenicillin is saturable and whether the effect of probenecid on the tubular excretion of benzylpenicillin is dose-dependent. 2 Each of four volunteers underwent three experiments. In each experiment benzylpenicillin was administered by continuous infusion, such that three different consecutive concentration levels were reached. In the first experiment no probenecid was given; in the second and third experiments, probenecid was administered by continuous infusion at a low and higher rate, respectively. 3 Plasma and urinary concentrations of benzylpenicillin were determined at 30 min intervals by high performance liquid chromatography. 4 By fitting the equation Rtub = Rtub,max.Cp/(EC50 + Cp) to the values of the tubular excretion rate found for benzylpenicillin (Rtub) vs the free plasma concentration (Cp), the values of Rtub,max and EC50 could be calculated: 3350 (+/- 606) mg h-1 for Rtub,max and 48.0 (+/- 17.8) mg l-1 for EC50 (in the absence of probenecid). 5 The EC50 for benzylpenicillin increased significantly with increasing doses of probenecid. 6 The dose of probenecid at which 50% of the excretory system is occupied by probenecid in the absence of benzylpenicillin (ED50) ranged from 13.2 to 108.5 mg h-1. 7 The EC50 of probenecid in one subject could actually be measured: 52.3 mg l-1. 8 Extrapolating these results to the clinical situation, the commonly used daily dose of 2 g of probenecid is likely to be close to the maximal effective dose for inhibition of the tubular excretion of benzylpenicillin.     

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.     

Increased rate of disappearance of serum probenecid in barbital dependent rats

Rats were made barbital dependent by administration of barbital in their drinking water. Subsequently, the rats were either not withdrawn (BN) or withdrawn from barbital for 24 h (BW-24). Before sacrifice, probenecid was administered to measure brain serotonin turnover. A statistically significant decrease in 5-hydroxyindole-acetic acid (5-HIAA) accumulation was observed in the cerebral cortex, medulla pons and midbrain. Subsequently, serum levels of probenecid were also measured by gas chromatography to determine if chronic barbital consumption might affect circulating probenecid. By ninety minutes following probenecid administration, serum probenecid levels in BN and BW-24 rats were significantly lower than control while a probenecid metabolite was significantly increased. The significantly reduced accumulation of 5-HIAA in brain areas of BN and BW-24 rats is probably the result of the more rapid decline of probenecid rather than a true decrease in serotonin turnover.     

Effect of probenecid on excretion and natriuretic action of furosemide

Summary Furosemide and inulin were given simultaneously by intravenous infusion to nine subjects over 2 h. The concentrations of sodium and of the two drugs in serum (free and protein bound) and in urine were followed during the infusion. In 6 male subjects the investigation was repeated after 3 days of oral treatment with probenecid 500 mg twice daily. Probenecid reduced the average ratio furosemide clearance/inulin clearance from 0.92 to 0.44. In experiments in which no probenecid had been given an average of 2% of the furosemide in urine was excreted by glomerular filtration. In vitro studies showed that the protein binding of furosemide was decreased in the presence of probenecid. The displacing effect of probenecid was confirmed in vivo, and during probenecid treatment glomerular filtration produced an average of 8% of the furosemide excreted by the kidney. The fraction of furosemide excreted by tubular secretion decreased during probenecid treatment from 98.0±0.6% to 91.7±5.6% (p<0.05). Prior to administration of probenecid, the fraction of the filtered sodium recovered from the urine during furosemide administration was 24.7%. Probenecid reduced that fraction to 21.0% (p<0.05). The excretion rate of furosemide appeared to be a better predictor of the natriuretic effect than its plasma concentration. Probenecid caused a significant change (p<0.05) in the regression line relating the log plasma concentration to the natriuretic effect, but it had no effect on the regression line relating the log urinary excretion rate of furosemide to its natriuretic effect. Although the decrease in the furosemide excretion rate during probenecid treatment averaged 25%, the sodium excretion rate was reduced by less than 15%. It is suggested that the natriuretic effect of furosemide is more pronounced if the furosemide molecules enter the tubular lumen at a more proximal level, and it is strongest if they do so by filtration through the glomerulus.     

Cephalexin: Human studies of absorption and excretion of a new cephalosporin antibiotic

1. Serum levels, half-lives and urine concentrations of cephalexin, an oral cephalosporin antibiotic which is unique in its absorption and excretion, are reported in human volunteers, fasting, non-fasting and non-fasting plus probenecid. Accumulation does not seem to occur.2. Cephalexin clearance was 376 ml./min and the ratio of cephalexin/creatinine clearances was 2.6 in one volunteer.3. Cephalexin had no effect on the urinary excretion of leucocytes, red cells or protein.4. The very high rate of absorption giving high serum levels and urine concentrations suggest cephalexin will be a useful antibiotic in susceptible bacterial infections in man.     

Effects of SCH27899 (Ziracin), an oligosaccharide everninomicin antibiotic,on urate kinetics in humans

Objective Intravenous administration of an everninomicin antibiotic, SCH27899 (Ziracin), in healthy subjects caused a marked decrease in serum urate by increasing its urinary excretion, as well as an increase in serum bilirubin in a dose-dependent manner. To clarify the underlying mechanism, a crossover study and an in vitro study were conducted.Methods Crossover study was performed in nine healthy male volunteers over three periods by administering SCH27899 (1-h i.v. infusion of 3 mg/kg) alone, probenecid (2000 mg, p.o.) alone and their combination. Also, an in vitro experiment was conducted using rat brush-border membrane vesicles to elucidate the effect of SCH27899 on urate transport across renal tubular epithelium.Results SCH27899 alone and probenecid alone showed a uricosuric, serum urate-lowering effect, and, when given in combination, the effects on serum urate appeared to be additive, as indicated in the earlier phase, prior to the peaks of respective drug effects. Serum and urinary concentrations of SCH27899 were not influenced by the co-administration of probenecid. Serum bilirubin was also significantly increased by both SCH27899 alone and in combination with probenecid. The SCH27899–probenecid combination additive effect on serum bilirubin did not reach significance. SCH27899, probenecid and losartan, an angiotensin-II-receptor antagonist possessing a uricosuric effect, significantly inhibited ¹⁴C-urate uptake into the vesicles, which was dependent on the pH gradient across the membrane; whereas, vancomycin did not.Conclusion It is concluded that SCH27899 itself contributes, at least in part, to a uricosuric effect following i.v. infusion. However, some metabolite(s) may also contribute to this, since the degree of urate-uptake inhibition by SCH27899 was less than probenecid and losartan, and the serum urate-lowering effect was delayed and prolonged compared with the time profile of serum concentration.     

Cefoxitin, a semi-synthetic cephamycin antibiotic. Metabolism in rats with renal insufficiency

The metabolism of cefoxitin, a new semi-synthetic cephamycin antibiotic, in rats with renal insufficiency was examined in comparison with that in control. Ascending urinary tract infection was produced in rats by intra-cystic inoculation with a virulent strain of Escherichia coli. In rats with severe infection progressed into purulent inflammation in the pelvis and medullar and cortical abscess formation, the urinary excretion of the antibiotic was reduced till the first 2 h after an i.v. dose of 40 mg/kg, while its serum levels and biliary excretion during this period were contrarily higher than those in rats with mild infection limited to pelvic inflammation and in control. On the other hand, in rats with renal arteriarctia produced by constriction of the renal artery with silver clip, blood levels of the antibiotic were higher than those in control. In the former animals, the urinary excretion was reduced to about a half, while the biliary excretion was increased up to twofold of that in control through the whole experimental period. In animals either with severe infection or with renal arteriarctia, the total recovery in the urine and the bile during 6 h of the experimental period was almost equal to those in mild infection or control groups.     

Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia.

Benzbromarone1 is a benzofuran derivative which lowers serum urate and increases urinary urate excretion in normal, hyperuricaemic and gouty subjects. In open short- and long-term studies benzbromarone reduced serum uric acid levels by one-third to one-half and maintained its effectiveness for periods of up to 8 years. Single-dose experimental studies have shown benzbromarone to have a urate-lowering effect similar to that of a therapeutic dose of probenecid or sulphinpyrazone, but unlike these drugs benzbromarone can be administered in a once daily regimen. In 2 short-term comparative therapeutic trials in a small number of patients with hyperuricaemia, 80mg of micronised benzbromarone daily was at least as effective as 1000mg of probenecid or 300mg of allopurinol daily in lowering serum uric acid levels. Side-effects during benzbromarone administration are usually mild and primarily gastrointestinal in nature.     

Probenecid interferes with the natriuretic action of furosemide

The interaction between probenecid and furosemide was studied in eight hospital patients (ages 20-65 years) who had been treated with oral furosemide, 40 mg daily, and moderate salt restriction for 10 days or longer. After stabilization of drug therapy and diet for at least 3 days, probenecid, 0.5 g twice a day, was given for 3 days and then discontinued. The 24-h urinary sodium excretion (UNaV) significantly decreased from 56.3 +/- 7.2 to 35.9 +/- 7.1 mmol/day when probenecid was added to the treatment regimen (p less than 0.01), and then significantly increased to 61.7 +/- 10.3 mmol/day after probenecid was discontinued (p less than 0.01). Parallel with the changes in UNaV, there were also significant corresponding changes (p less than 0.01) in urinary excretion of uric acid (392.4 +/- 46.5, 600.9 +/- 102.1, and 345.0 +/- 33.2 mg/day, respectively), renal clearance of uric acid (3.7 +/- 0.3, 14.3 +/- 2.4, and 4.1 +/- 0.3 ml/h/kg, respectively), and serum uric acid concentration (7.7 +/- 0.5, 3.3 +/- 0.2, and 6.3 +/- 0.3 mg/dl, respectively). Before and after discontinuing probenecid therapy, there were no significant differences in these parameters (p greater than 0.05). In conclusion, the natriuretic action of furosemide was attenuated by concurrent probenecid therapy, probably owing to a reduction of furosemide delivery to the luminal side of renal tubules.     

Effect of probenecid on the disposition of captopril and captopril dimer in the rat

The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.     

Serum and bone concentrations of teicoplanin and vancomycin: study in an animal model

Teicoplanin and vancomycin are antibiotics widely used in the therapy of bone and joint infections. The aim of this study was to compare bone and serum concentrations of each antibiotic in guinea pigs after administration of 50 mg/kg of teicoplanin or vancomycin by the intravenous route. Serum and bone concentrations were determined immediately before and 0.5, 1, 2, 6, 12 and 24 h after drug administration by means of high performance liquid chromatography. Teicoplanin concentrations were always higher than vancomycin levels. Area under the concentration/time curve was significantly greater for teicoplanin than for vancomycin. In bone, teicoplanin concentration increased up to 6 h, while vancomycin reached its peak after 2 h. Moreover, teicoplanin showed markedly higher levels at 6, 12 and 24 h than vancomycin. In conclusion, the ability of teicoplanin to penetrate bone in greater amount than vancomycin confirms the potential use of teicoplanin in the treatment of bone infections and in the prophylaxis of orthopedic surgery.     

The effect of crystal size, gastric content and emptying rate on the absorption of nitrofurantoin in healthy human volunteers

The effect of four crystal sizes, gastric contents, and gastrointestinal motility on the absorption and excretion of nitrofurantoin was studied in three separate cross-over studies on 10 healthy volunteers. Microcrystal preparation gave an early and high serum peak. The greater the crystal size was, the smaller was the peak serum concentration. Correspondingly, microcrystal preparations gave initially very high nitrofurantoin concentrations in urine. Macrocrystal preparation had a not significantly longer excretion time than the other preparations. Food did not increase the serum nitrofurantoin concentrations, but excretion during 4 to 6 h was considerably greater than after fasting. In contrast, antacid and the use of a delayed-release preparation greatly worsened the biovailability of nitrofurantoin. An increased gastric emptying rate induced by metoclopramide significantly worsened the absorption of nitrofurantoin, but atropine only retarded the absorption and the principal excretion in urine occurred during 4 to 8 h.     

Lack of probenecid effect on nonrenal excretion of ceftriaxone in anephric patients

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h X 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model-independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.     

Effect of probenecid on the excretion of ampicillin in human bile

1. Ampicillin concentrations were determined in serum and bile after intravenous injection into patients with T-tube bile drainage of 1 gram ampicillin before and during probenecid medication. The concentrations were followed up to fifteen hours after injection.2. Probenecid increased the half-life of ampicillin in serum from 74 minutes to 137 minutes.3. Ampicillin concentrations in bile were higher following probenecid medication and a concentration over 5 mug/ml was obtained for 3 h longer than before probenecid.4. The ampicillin concentrations in bile were approximately the same as those in serum both before and during probenecid medication suggesting passive transport of ampicillin from blood to bile.5. A combined treatment of ampicillin and probenecid might be of clinical value in the therapy of cholangitis and typhoid carriers.