A dissolution anomaly involving ticrynafen in simulated intestinal fluid without enzyme.

Data are presented showing that the anomalous dissolution behavior of ticrynafen in simulated intestinal fluid without enzyme is due to the presence of potassium ions in the dissolution medium. Solubility studies indicate that an insoluble 1:1 complex is formed between ticrynafen and its potassium salt. This complex apparently creates an insoluble barrier that prevents complete dissolution of ticrynafen. To determine whether this might also occur in clinical use, a three-way cross-over study in 12 subjects was done. Data from this investigation show that concomitant administration of ticrynafen tablets and potassium in the form of a commercial supplement does not adversely affect bioavailability.

Renal sites of natriuretic and uricosuric activity of ticrynafen in the mongrel dog.

Following establishment of steady state plasma concentrations of ticrynafen in the mongrel dog, the intravenous injection of large doses of p-aminohippurate (PAH) or sodium salicylate reduced or blocked the urinary excretion of ticrynafen. In a similar manner, the intravenous administration of ticrynafen reduced the urinary excretion of PAH in preloaded dogs. Since PAH and salicylate are actively secreted by a renal tubular organic anion transport system, these data were interpreted as evidence of an active tubular secretion of ticrynafen. The natriuresis and uricosuria which result from the administration of ticrynafen to the mongrel dog were reduced by PAH and salicylate at doses of these compounds which effectively blocked the secretion of ticrynafen. These results demonstrate that in the dog, the natriuretic and uricosuric activity of ticrynafen results from the presence of ticrynafen in the tubular lumen.

Pharmacokinetics and mode of action of tienilic acid.

A review of the absorption, distribution, metabolism and excretion of ticrynafen (tienilic acid) in 8 animal species, including man, is presented. Although some species effects are apparent, ticrynafen absorption is essentially complete following oral administration. The compound is extensively bound to plasma proteins, primarily albumin. Consequently, tissue concentrations are generally lower than plasma concentrations. Plasma and whole body clearance of ticrynafen is rapid due both to metabolism and to extensive renal excretion of the compound and its metabolites. Male/female differences in renal excretion occur, with a subsequent effect on ticrynafen metabolism. Ticrynafen is an inhibitor of reabsorption of sodium and uric acid by the kidney. This inhibitory effect, within the renal tubular lumen, accounts for its diuretic and uricosuric activity and could account for its antihypertensive activity, although a direct effect has also been claimed. Ticrynafen is also a classical example of a competitive inhibitor of organic acid transport in the kidney and other organs. Much of the drug-drug interaction involving ticrynafen is understandable due to its effect on transport. However, potentiation of anticoagulant activity appears to involve some direct effects upon warfarin metabolism although ticrynafen, in general, is not an enzyme inducer or inhibitor. Toxicity of ticrynafen is low in all animal species.