Metabolie Effects in Man of Tienilic Acid, a New Diuretic with Uricosuric Properties

Lemieux, Guy; Gougoux, A.; Vinay, Patrick; Kiss, André; Baverel, Gabriel

doi:10.1159/000184854

Cited by 13 publications

(7 citation statements)

References 24 publications

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“…Tienilic acid has the same hypotensive (1 ,5) and hypocalciuric effect (1) in man as the thiazides. In contrast to the currently available diuretics which induce hyperuricemia, tienilic acid lowers plasma urate level significantly (1,5). In a previous study, the uricosuric effect of the drug, in the dog, was shown to occur in the proximal tubule (6).…”

Section: Introductionmentioning

confidence: 93%

Metabolism of tienilic acid (ticrynafen) in man. Pharmacokinetic and mass spectrometric studies

Vinay

Paquin

Lemieux

et al. 1980

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetics and metabolism of tienilic acid (ticrynafen) a new diuretic with uricosuric properties, were studied in human volunteers following single ingestion of 250, 500 or 1000 mg. Tienilic acid was found to be extentively (more than 98%) bound to plasma proteins but not to displace the fraction of urate bound to plasma proteins at the usual therapeutic dosage (250 to 500 mg), The uricosuric and natriuretic effects of the drug lasted 8 to 12 hours. A peak concentration of 2.5, 4.5 or 10.1 mg/dl was noted in the plasma 2 hours following ingestion of each dose. The apparent volume of distribution of the drug was close to that of plasma volume. Tienilic acid disappeared rapidly from the plasma according to a first order kinetics and the plasma half-life ranged from 1.6 to 2.4 hours. Gas chromatography and mass spectrometric studies revealed that 21% of the ingested tienilic acid is excreted as such in the urine over 24 hours. Three major metabolites of the drug were identified in the urine: a monohydroxylated, a dihydroxylated and a diacid product. Including metabolites, 36 to 47% of the drug was excreted in the urine within 24 hours. No significant glucuro or sulfoconjugation of the drug or its metabolites could be detected in the urine. Excretion of the drug and its metabolites was also noted in the bile. It is concluded that tienilic acid is rapidly metabolized and excreted in humans with normal kidney and liver function.

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Section: Introductionmentioning

confidence: 93%

Metabolism of tienilic acid (ticrynafen) in man. Pharmacokinetic and mass spectrometric studies

Vinay

Paquin

Lemieux

et al. 1980

European Journal of Drug Metabolism and Pharmacokinetics

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“…An increase of potassium excretion was reflected in a significant reduction of serum potassium, an effect which in an earlier study was similar to that of hydrochlorothiazide. 5 An increase of serum calcium was associated with the acknowledged hypocalciuric action of tienilic acid,5 another property which it shares with thiazide diuretics.10 Phosphate excretion was unaffected.…”

Section: Discussionmentioning

confidence: 99%

Tienilic acid: a single treatment for hyperuricaemia and hypertension?

Gibson¹,

Rodgers²,

Potter³

et al. 1980

Annals of the Rheumatic Diseases

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A relationship between hyperuricaemia and hypertension has been observed in population surveys,1 2 and in studies confined to both hypertensive3 and gouty subjects.4 When these 2 disorders coincide, diuretic therapy for hypertension may be injudicious because it may accentuate hyperuricaemia unless a concurrent hypouricaemic agent is prescribed.Tienilic acid is a new diuretic with hypotensive and marked hypouricaemic properties.5 For this reason it has been proposed as the drug of first choice in patients with hypertension who already have gout or are likely to develop it when taking thiazide diuretics.6 The study reported here was an attempt to determine whether tienilic acid alone may be adequate treatment for the hyperuricaemia of gouty patients and to guage its effect on the hypertension which may be associated with gout. Patients and methodsSeventeen male patients with a history of recurrent acute gout and sustained hyperuricaemia entered the study, which was conducted on an outpatient basis.Their mean age was 54 (range 31-69) years. Eleven

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“…The numbers of assays are given in parentheses. 10.00 * j'J2 u?) 3 ' 44± L93 (4) 4.13*J£(10) 2 -44 *L26 (17) 3-hydroxybutyrate dehydrogenase was found to be inversely distributed along the proximal tubule.…”

Section: Distribution Of Enzymesalong the Mouse Nephronmentioning

confidence: 99%

“…Die 3-Oxosäure-CoA-Transferase wurde mit einer radiochemischen Methode gemessen, bei der die Acetacetyl-CoA-abhängige Umwandlung von [l, [4][5][6][7][8][9][10][11][12][13][14] Mammalian kidney plays a significant role in ketone body metabolism. By its reabsorptive and excretory functions, the kidney regulates blood ketone levels' 1 '.…”

Section: Ketonkörper-stoffivechsel Der Niere Verteilung Der 3-oxosäuunclassified

“…After washing the column with 200 ml distilled water D-3-hydroxybutyrate was eluted with 200 ml of a linear gradient of 0.1-IM KHCO 3 , and the eluates collected in 10 ml portions. D-Hydroxybutyrate and acetoacetate were measured enzymatically in each fraction' * 8 l The combined fractions containing D-3-hydroxybutyrate and no acetoacetate (usually fraction [4][5][6][7][8][9][10][11][12][13][14] were combined, the pH brought to 7 with 3M KOH after acidification with HC1O 4 , (final concentration 0.3M). After centrifugation the clear supernatant was lyophilized.…”

Section: -Hydroxybutyrate Dehydrogenasementioning

confidence: 99%

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Renal Ketone Body Metabolism. Distribution of 3-Oxoacid CoA-Transferase and 3-Hydroxybutyrate Dehydrogenase along the Mouse Nephron

Guder¹,

Pürschel²,

Wirthensohn³

1983

Hoppe-Seyler´s Zeitschrift für physiologische Chemie

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Two enzymes of ketone body metabolism, 3-oxoacid CoA-transferase and 3-hydroxybutyrate dehydrogenase were measured with ultramicromethods to map their activities along single, dissected segments of mouse nephron. 3-Oxoacid CoA-transferase activity was assayed with a radiochemical procedure by separating [ l4 C]succinyl-CoA, formed in the presence of acetoacetyl-CoA from [l,4-14 C]succinate.This procedure, when compared to the spectrophotometric method, resulted in similar activities in , mouse organ homogenates. 3-Hydroxybutyrate dehydrogenase activity was determined with sufficient sensitivity by using NADH-dependent luciferase. The dehydrogenase exhibited only 5% of the activity of the 3-oxoacid CoA-transferase when measured in mouse kidney cortex homogenates.Both enzymes were found to be present in all nephron structures studied. The specific activitiy related to tubular protein, which was determined in parallel in all segments dissected, exhibited a typical distribution pattern along the nephron. Both enzymes roughly paralleled each other along the structures of the distal nephron. They exhibited high activities in the thick ascending limb of Henle's loop and the distal convoluted tubule, but decreased to nearly 20% in the segments of the collecting tubule. In the proximal convoluted and straight tubule 3-oxoacid CoAtransferase activity was almost equal. In contrast, 3-hydroxybutyrate dehydrogenase increased by a factor of 5 from the convoluted to the straight portion. This heterogeneity along the proximal tubule remained when pure D-hydroxybutyrate was used as substrate, but was not found when rat or rabbit nephron segments were analysed. Lowest activities of enzymes were recovered from glomeruli and thin descending limbs of Henle's loop. The results obtained allow for the conclusion that 3-hydroxybutyrate and acetoacetate can be metabolized in all structures of the mouse nephron with different capacities in various segments. With the exception of the relatively low activity of 3-hydroxybutyrate dehydrogenase in the proximal convoluted tubule, the distribution pattern mirrors the distribution of mitochondria along the rat nephron. The results point to the possible role of ketone bodies as energy fuels for nephron segments performing active transport processes.Zusammenfassung: Für zwei Enzyme des Ketonkörper-Stoffwechsels, 3-Oxosäure-CoA-Transferase und 3-Hydroxybutyrat-Dehydrogenase wurden Ultramikroverfahren entwickelt, um ihre Aktivität in einzelnen mikrodissezierten Abschnittten des Nephrons der Maus zu bestimmen. Die 3-Oxosäure-CoA-Transferase wurde mit einer radiochemischen Methode gemessen, bei der die Acetacetyl-CoA-abhängige Umwandlung von [l,4-14 C]Succinat in [ 14 C]Succinyl-CoA als Maß der Enzymaktivität diente. Dieses Verfahren lieferte in Homogenaten von Mäuseorganen gleiche Aktivitäten wie der spektrophotometrische Test. Die 3-Hydroxybutyrat-Dehydrogenase konnte mit Hilfe der Biolumineszenz NADH-abhängiger Luciferase mit ausreichender Sensitivität bestimmt werden. Die Dehydrogenase weist in Nie...

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Metabolie Effects in Man of Tienilic Acid, a New Diuretic with Uricosuric Properties

Cited by 13 publications

References 24 publications

Metabolism of tienilic acid (ticrynafen) in man. Pharmacokinetic and mass spectrometric studies

Metabolism of tienilic acid (ticrynafen) in man. Pharmacokinetic and mass spectrometric studies

Tienilic acid: a single treatment for hyperuricaemia and hypertension?

Renal Ketone Body Metabolism. Distribution of 3-Oxoacid CoA-Transferase and 3-Hydroxybutyrate Dehydrogenase along the Mouse Nephron

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