'Benemid', p-(di-n-propylsulfamyl)-benzoic Acid: Inhibition of Glycine Conjugative Reactions

Beyer, Karl H.; Wiebelhaus, Virgil D.; Tillson, Elizabeth K.; Russo, Horace F.; Wilhoyte, Katharine M.

doi:10.3181/00379727-74-18043

Cited by 32 publications

(9 citation statements)

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“…The tubular secretion of other weak organic acids (P AH, phenolsulphonphthalein, salicylic acid, pantothenic acid, uric acid, etc.) was found to be inhibited by probenecid (Beyer et al, 1950;Boger et aI., 1 950a,b;Gutman et aI., 1955). Of these, in particular, the uricosuric effect of probenecid was extensively evaluated and found to be some 6-fold higher than the related drug carinamide (Bishop et al, 1951;Gutman, 1950Gutman, , 1951a Yu, i 95 i; Taihott ei ai., i 95 i; Wolfson et ai., 1948).…”

Section: Heparinmentioning

confidence: 92%

“…The latter antibiotic is extensively conjugated in the liver with glycine; the conjugate is therapeutically active and is rapidly excreted by the kidney with renal clearance approximating that of renal blood flow (Boger et aI., 1950a,b). The increase in plasma levels of PAS can be explained by in vitro experiments in which it was found that probenecid inhibits glycine conjugation (Beyer, 1954;Beyer et al, 1950). It was shown by Schachter and Taggart (1953) that 'the inhibition of hippurate synthesis by carinamide and probenecid in respiring or ATP-driven systems must be due to an interference with benzoate activation rather than the condensation reaction' ... and ... 'carinamide and probenecid interfere with the activation of acetate by A TP'.…”

Section: The Earliest C1irical Application Of Probenecid Wasmentioning

confidence: 96%

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Clinical Pharmacokinetics of Probenecid

Cunningham

Israili

Dayton

1981

Clinical Pharmacokinetics

216

146

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A review of the clinical applications and of the disposition of probenecid in man, including drug interactions, is presented. Probenecid is the classical competitive inhibitor of organic acid transport in the kidney and other organs. There are 2 primary clinical uses for probenecid: as a uricosuric agent in the treatment of chronic gout and as an adjunct to enhance blood levels of antibiotics (such as penicillins and cephalosporins). Adsorption of probenecid is essentially complete following oral administration. The drug is extensively metabolised by glucuronide conjugation and by oxidation of the alkyl side chains; oxidation of the aromatic ring does not occur. The half-life of probenecid in plasma (4 to 12 hours) is dose-dependent. Renal excretion is the major route of elimination of the metabolites; excretion of the parent drug is minimal and is dependent on urinary pH. Probenecid and its oxidised metabolites are extensively bound to plasma proteins, mainly to albumin. Tissue concentrations (based on animal studies) are generally lower than plasma concentrations. Most of the drug-drug interactions involving probenecid are due to an effect on the kidney-block of transport of acidic drugs. Similarly probenecid affects the tubular secretion of a number of acidic endogenous substances by the kidney. Probenecid is also involved in the block of transport of acidic metabolites of catecholamines, for example homovanillic and hydroxyindoleacetic acids, in the brain. There are a number of analytical procedures for the assay of probenecid. These are based on spectrophotometry, spectrofluorometry, gas and liquid chromatography and radioimmunoassay.

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Section: Heparinmentioning

confidence: 92%

Section: The Earliest C1irical Application Of Probenecid Wasmentioning

confidence: 96%

Clinical Pharmacokinetics of Probenecid

Cunningham

Israili

Dayton

1981

Clinical Pharmacokinetics

216

146

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“…Probenecid [p-(dipropylsulfamoyl)benzoic acid] has been found to inhibit the tubular secretion of a variety of weak organic acids (e.g., para-aminohippuric acid, chlorothiazide, phenolsulphonphthalein, salicylic acid, pantothenic acid) (1)(2)(3)8). It has been widely used as a uricosuric agent and as an adjunct to therapy with penicillin and other antibiotics to enhance antibacterial concentrations in plasma (4).…”

mentioning

confidence: 99%

Effect of probenecid on the pharmacokinetics of cefmenoxime

Sennello¹,

Quinn²,

Rollins³

et al. 1983

Antimicrob Agents Chemother

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In this study, we were concerned with the effect of probenecid on the pharmacokinetics of 1,000 mg of cefmenoxime administered over a 30-min period by intravenous infusion. Each of a total of 10 subjects received cefmenoxime twice, once with and once without adjunctive probenecid. The data were fit by iterative nonlinear regression procedures to a two-compartment open pharmacokinetic model, with elimination from the central compartment. The mean calculated peak concentration, area under the curve from zero to infinity, and half-life without probenecid were 78.1 pg/ml, 77.2 zg h/ml, and 1.14 h, respectively. When cefmenoxime was administered with probenecid, these values were 86.7 ,i.g/ml, 158.2 ,ug * h/ml, and 1.78 h, respectively. Averages of about 55 and 46% of the administered doses were recovered in urine samples collected at 0 through 24 h for doses administered without and with probenecid, respectively. The mean corrected renal drug clearance was 159 and 66 ml/min without and with probenecid, respectively. Statistical significance (P < 0.05) was demonstrated for the differences in beta half-life, (K/net), calculated peak concentration, area under the curve from 0 to infinity, and renal clearance, but not for K21, K12, volume of distribution, or alpha-phase distribution rate constant. The results of this study indicate that tubular secretion is the predominant mechanism of clearance for cefmenoxime and that probenecid alters the pharmacokinetics of the compound by competitively inhibiting its tubular secretion without affecting either the rate or

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“…Conjugation to glycine is a well known detoxication mecha nism which can take place both in the liver and in the kidney. In some instances this conjugation can be prevented by adm inistration of probenecid (Benemid) (Beyer et al, 1950;Bishop and Rand, 1951). B ut this is not possible with the conversion of IProAc to IAcrGly; we tried it in two cases with rather high doses of Benemid.…”

Section: Origin O F Indolyl-3-acryloyl-glycinementioning

confidence: 99%