Pyrazinamide excretion

Absorption/Distribution - Pyrazinamide is well absorbed from the Gl tract and attains peak plasma concentrations within 2 hours. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid. Pyrizinamide is approximately 10% bound to plasma proteins. Metabolism/Excretion - The half-life is 9 to 10 hours it may be prolonged in patients with impaired renal or hepatic function. 

Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration, within 24 hours. Pyrazinamide is significantly dialyzed and should be dosed after hemodialysis. 

Hyperuricemia Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia that is usually asymptomatic. Patients started on pyrazinamide should have baseline serum uric acid determinations. Discontinue the drug and do not resume if signs of hyperuricemia accompanied by acute gouty arthritis appear. 

Pyrazinamide can only be administered orally. It has a protein binding of 10-20% and is widely distributed, also to the CNS. Pyrazinamide undergoes deamination and oxidation in the liver with urinary excretion of the metabolites. Its elimination half-life is approximately 10 h. Combination with other drugs is mandatory as resistance occurs rapidly. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

Pyrazinamide is well absorbed from the GI tract and is widely distributed throughout the body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on the intracellular organisms its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are excreted primarily by renal glomerular filtration. 

Hepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy. 

Blood urate concentrations can be increased because of reduced excretion of uric acid in patients taking ethambutol (390). This is probably enhanced by combined treatment with isoniazid and pyridoxine. Special attention should be paid when tuberculostatic drug combinations include pyrazinamide. However, severe untoward clinical effects are rare, except in patients with gout or renal insufficiency (391,392). 

Pyrazinamide interferes with the renal excretion of urate, resulting in hyperuricemia. Acute episodes of gout or arthralgia have occurred. Arthralgia responds better to NSAIDs than to uricosuric drugs (997). 

On June 6, this patient developed severe loin pain after he participated in two 150-m sprints at a town athletics meeting. After 5 days, he was referred to the outpatient clinic of our department. His serum creatinine and uric acid levels and FEUA, were 2.9mg/dl, 2.1 mg/dl, and 49.7%, respectively. His creatine phosphokinase (CPK) level was normal. When his serum creatinine level decreased to 1.58 mg/dl, a contrast medium was administered. A delayed computed tomography (CT) scan after 24 and 48 h confirmed patchy wedge-shaped contrast enhancement (Fig. 58). Under a diagnosis of ALPE, his body water balance (hydration) was controlled. In this patient, recovery was achieved 4 weeks after onset, and his serum creatinine and uric acid levels were then 1.0 mg/dl and 0.6 mg/dl, respectively. Furthermore, load tests with a uric acid reabsorption inhibitor (benzbromarone) and a uric acid excretion inhibitor (pyrazinamide) suggested presecretory reabsorption defect-related renal hypouricemia. A kidney biopsy 16 days after onset confirmed the recovery from acute tubular necrosis. 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

Pyrazinamide is distributed throughout the body. Peak plasma concentrations are reached 2 hours after oral administration. Excretion is primarily by glomerular filtration. Serum concentrations are generally 30-50 gg/ml with daily doses of 20-25 mg/kg. The maximum daily dose should not exceed 3 g, regardless of weight. At a pH of 5.5, the minimal inhibitory concentration of pyrazinamide for Mycobacterium tuberculosis is 20 pg/ml (1). 

PharmacoWnetics Pyrazinamide is well absorbed orally and penetrates most body tissues, including the CNS. The drug is partly metabolized to pyrazinoic acid, and both parent molecule and metabolite are excreted in the urine. The plasma half-life of pyrazinamide is increased in hepatic or renal failure. 

Pyrazinamide is readily absorbed after oral administration, but little of the intact molecule is excreted unchanged (Fig. 41.9). The major metabolic route consists of hydrolysis by hepatic microsomal pyrazinamidase to pyrazinoic acid, which may then be oxidized by xanthine oxidase to 5-hydroxypyrazinoic acid. The latter compound may appear in the urine either free or as a conjugate with glycine (23). 

Pyrazinamide is an antituberculosus drug which may induce hyperuricemia. The active substance, in fact, is pyrazinoic acid, a metabolite of pyrazinamide (Weiner and Tinker, 1972). When a large dose of pyrazinamide (3g) is administered to man, the concentration of pyrazinoic acid in the plasma reaches 10 to 20 mg/liter (Prasad et al., 1977), and the urinary excretion of urate falls to 20% of its control value, the fractional excretion of urate (FEurate) to 2-3% (Steele, 1978). The PZA suppressible excretion of urate represents only a fraction of the total secretion because it does not comprise the part of secreted urate which is reabsorbed. Only if the secretory transport were located below... 

Is the secretory transport in man and chimpanzee quantitatively important The fact that in the chimpanzee, which normally excretes 10% of the amount filtered, it is possible to increase the fractional excretion to 150% by mersalyl (a mercurial diuretic) points to an important secretory capacity (Fanelli et al., 1973). In man, secretion, is required for maintaining urate homeostasis since patients treated with pyrazinamide for tuberculosis may develop hyperuricemia (Emmerson, 1978 review). Furthermore, a retention of urate is observed when diuretics are given over long periods. Part of the retention is secondary to volume depletion and a stimulation of reabsorption (Steele, 1978), but at least in the case of thiazides a direct inhibition of the secretory transport cannot be excluded (Emmerson 1978, review). Such an effect was shown to occur in the rat (Weinman et al. 1975, 1976). 

Glomemlar filtration rate (GFR) was estimated through endogenous creatinine clearance and the rate of urate filtration from GFR and semm urate. The pyrazinamide suppres-sible part of the urate excretion was the intial excretion (UV-ur) minus the minimum excretion during PZA suppression (UV-ur, min). The tubular reabsorption of filtered urate (TR-ur) was calculated from GFR and the minimum urate clearance during PZA... 

Patients with a proximal renal tubular acidification defect had a basal urate excretion not different from controls or hyperuricosuric patients. Their response to pyrazinamide was, however, more pronounced than in controls and hyperuricosuric patients. The calculated tubular reabsorption of filtered urate was higher than in both controls and hyperuricosuric patients. It is suggested that this may contribute to the higher serum urate and the lower urate clearance in stone formers with a proximal renal acidification defect compared to patients with a normal acidification of the urine that we have reported on previously (4). 

Fifty patients (22 males and 28 females mean age 46 years) were consecutively referred to our Metabolic Unit for the evaluation of recurrent nephrolithiasis. Diagnosis was made on the basis of spontaneous emission or chirurgical extraction of two or more calculi with an interval superior to one year. In every patient we performed a metabolic study and the results were compared with those obtained in 20 controls (10 males and 10 females mean age 33 years) Hyperuricosuria was defined as daily uric acid excretion above 800 mg for men and 750 mg for woman, while on a purine-free diet. Renal handling of uric acid ms evaluated by means of pyrazinamide (PZA) and probenecid (PB) tests. ... 

The patient was placed on an essentially purine-free diet and received no medication for 5 days. Uric acid metabolism disclosed uricemia 2.0 mg/dl uricosuria 510 mg/day Cur 15.4 ml/min Ccr 91 ml/min fractional excretion of uric acid (Cur/Ccr) 16.9%. Basal plasma calcitonin was 168 pg/ml (normal values undetectable). A pentagastrin bolus injection of 0.5 g/Kg elevated plasma calcitonin over 1000 pg/ml. Simultaneously, serum uric acid decreased from 2.0 mg/dl to 1.3 mg/dl, and Cur/Ccr increased from 16.9% to 25.7%. A pentagastrin test in two control subjects did not make plasma calcitonin levels detectable, nor did it modify uric acid excretion. Her clinical course was progressively down-hill and she died after several bronchoneumonic episodes and massive tracheal hemorrage. Pyrazinamide and probenecid tests could not be done. Permission for autopsy was denied. 

Hypouricemia and the Effect of Pyrazinamide on Renal Urate Excretion... 

The nature of the renal lesion in Wilson s disease has not been established since net urate excretion reflects filtration, reabsorption and secretion from the tubule in a manner which is not entirely clear. Recently pyrazinamide (PZA) which depresses urate excretion by 957o has been used to examine urate transport (2). At the time these studies were begun it seemed clear that pyrazinamide selectively inhibited urate secretion virtually completely, while not affecting reabsorption. Other studies had suggested that this secretory component was distal to any reabsorp-tive sites (3). Further analysis of this drug has led to some reservations concerning both of these points so that analysis of the actual mode of action of PZA will be critical to any analysis of the site of altered urate transport in these patients with Wilson s disease. 

We have studied filtration and excretion of urate with and without pyrazinamide in 10 patients with Wilson s disease in order to determine if the urate transport defect persists after treatment with D-penicillamine and to make some judgement concerning the site of any defect in urate handling by the renal tubule. 

Secreted urate (Ts urate) was calculated as the amount of urate excreted per ml GFR before pyrazinamide minus the amount excreted per ml GFR after the drug was given (during the period where maximal suppression of urate was apparent). Tubular reabsorption (Tr) was expressed as a percent of filtered load. This was calculated as the amount of urate filtered (assuming no protein binding) minus the excreted urate at the point where maximal suppression was evident. Fractional excretion of urate was expressed as the percent of filtered load excreted during pyrazinamide administration. Urine samples for amino acid excretion were collected within three months of the urate studies while patients were off D-penicillamine. The amino acids were measured on a Phoenix amino acid analyser. 

Pyrazinamide virtually abolished the difference in urate excretion between the two groups. The fractional excretion of... 

There are other ways that urate excretion could be altered. Plasma urate binding could be different in these patients or altered in a different way by pyrazinamide, but we have no studies relevant to this point. 

In 1961 Gutman and Yu proposed a three component system for the regulation of the renal excretion of uric acid in man. The first component of this system is filtration of plasma urate at the glomerulus. While this process is certain to be operative in the human kidney, its quantitative role in the renal excretion of uric acid in man depends upon the extent of urate binding to plasma proteins in vivo. This is a subject that is being discussed in another section of this symposium and will not be considered further in this paper. The second and third component of this system relate to uric acid reabsorption and secretion by the human nephron. Ample data is available to document that both of these processes are operable in the human kidney (Gutman and Yu, 1957 Gutman, et al., 1959), but the relative contribution of each to the final excretion of uric acid has been difficult to determine with conventional clearance techniques. However, a potential solution to this problem of bidirectional uric acid transport appeared in 1967 when Steele and Rieselbach introduced the "pyrazinamide suppression test . 

The test is performed by determining uric acid excretion before and after the administration of pyrazinamide or its metabolite pyrazinoic acid (PZA) in a dosage sufficient to give maximal suppression of uric acid excretion. The decrement in uric acid excretion after PZA administration is taken as a quantitative measure of uric acid secretion. In addition the difference between filtered load of uric acid and uric acid excretion at the time of maximal PZA effect is taken as a quantitative measure of uric acid reabsorption. These estimates of uric acid secretion and reabsorption assume the following conditions (Table 1) ... 

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