Observations on the Disposition of Probenecid in Patients Receiving Allopurinol

Tjandramaga, T. B.; Cucinell, Samuel A.; Israili, Zafar H.; Perel, James M.; Dayton, Peter G.; Yu, Tzy‐Chyi; Gutman, Alexander B.

doi:10.1159/000136342

Cited by 25 publications

(15 citation statements)

References 5 publications

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“…8) tase are responsible for much of the O2 normally produced by microsomes, and thus might be sources of O2 production during reperfusion injury (37). In this regard, it is interesting to note that allopurinol is a known inhibitor of P-450 metabolism (38,39). Other potential microsomal sources of°2 are peroxidases associated with AA metabolism (40), which have been hypothesized as sources of O°generated during reperfusion of ischemic brain (21).…”

Section: Discussionmentioning

confidence: 99%

Role of reactive oxygen species in reperfusion injury of the rabbit lung.

et al. 1989

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We have developed a model of reperfusion injury in Krebs buffer-perfused rabbit lungs, characterized by pulmonary vasoconstriction, microvascular injury, and marked lung edema formation. During reperfusion there was a threefold increase in lung superoxide anion (0°) production, as measured by in vivo reduction of nitroblue tetrazolium, and a twofold increase in the release of 02 into lung perfusate, as measured by reduction of succinylated ferricytochrome c. Injury could be prevented by the xanthine oxidase inhibitor allopurinol, the 02 scavenger SOD, the hydrogen peroxide scavenger catalase, the iron chelator deferoxamine, or the thiols dimethylthiourea or Nacetylcysteine. The protective effect of SOD could be abolished by the anion channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid, indicating that SOD consumes 02 in the extracellular medium, thereby creating a concentration gradient favorable for rapid diffusion of 02 out of cells. Our results extend information about the mechanisms of reperfusion lung injury that have been assembled by studies in other organs, and offer potential strategies for improved organ preservation, for treatment of reperfusion injury after pulmonary thromboembolectomy, and for explanation and therapy of many complications of pulmonary embolism.

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Section: Discussionmentioning

confidence: 99%

Role of reactive oxygen species in reperfusion injury of the rabbit lung.

et al. 1989

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“…Probenecid is highly lipid-soluble; kp (chloroform/0.15 M HCO > 2000 (Dayton et al, 1963;Weiner et al, 1960). The distribution ratio in peanut oil/pH 7.4 Sorensen buffer = 0.03 for probenecid (Israili et al, 1972). The pKa of probenecid is 3.4 (aqueous medium, Shore et al, 1957) and5.8 (aqueous-methanol, Dayton et al, 1966).…”

Section: Physicochemical and Pharmacokinetic Properties Of Probenecidmentioning

confidence: 99%

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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“…Allopurinol extends the half-life of Benemid and potentiates its uricosuric effect, whereas Benemid increases the clearance of oxypurinol diminishing the inhibition of xanthine oxidase [ 608,655 ] . These mechanisms would suggest that the usual doses of allopurinol should be increased, whereas standard doses of Benemid should be decreased.…”

Section: Allopurinolmentioning

confidence: 99%

Management of Hyperuricemia and Gout

Newcombe¹

2012

Gout

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Observations on the Disposition of Probenecid in Patients Receiving Allopurinol

Cited by 25 publications

References 5 publications

Role of reactive oxygen species in reperfusion injury of the rabbit lung.

Role of reactive oxygen species in reperfusion injury of the rabbit lung.

Clinical Pharmacokinetics of Probenecid

Management of Hyperuricemia and Gout

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