Pharmacokinetic study of 2,3-dichloro 4- (2-thienyl keto14C) phenoxyacetic acid (tienilic acid) in animals

Abstract

The metabolic fate of a new diuretic, tienilic acid, was investigated in Wistar rats, Swiss mice, Beagle dogs, and large white pigs using the 14C-labelled compound. Tienilic acid and its metabolites were determined in bile, urine, and plasma following intravenous and oral administration. In general, only a small amount of unmetabolized drug is excreted. Biotransformation consists of two major metabolic routes; one is reduction and the other is oxidative hydrolysis of the molecule at the level of the carbonyl group. These two routes co-exist in all species studied, but the reduction route is prominent in the dog. Mass spectrometry was used to elucidate the structure of two metabolites and confirm it for the third.

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

“…Electron energy was 70 eV, trap current 250 IlA and source temperature 250"C. Under these conditions, the retention times of the compounds were similar to those already described. The mass spectra obtained in the urine extract for tienilic acid and its two known metabolites were identical to those observed with the pure compounds and are in agreement with those obtained by Levron et al for the same metabolites (11). The mass-spectrum obtained for the unknown metabolite showed a molecular ion at m/e 506 with an isotope cluster corresponding to two chlorine atoms, thus relating this compound to tienilic acid.…”

“…This assumption seems reasonable in view of the fact that both molecules carry two chlorines each which are mainly responsible for the BCD response. Total recovery of the drug including the metabolites averaged 3670 with the single 250 mg dose of tienilic acid and 47%, with 500 mg. No significant glucuro or sulfoconjugated forms of either tienilic acid or its metabolites could be detected in the urine which is in accord with the fmdings of Levron et al in dog, pig, rat and mouse (11). Figure 3 shows the plasma disappearance curve of tienilic acid as a function of time.…”

“…The monohydroxylated and the diacid form have already been identified in laboratory animals (11) and synthetized (Smith, Kline and French, Philadelphia, Pa.) but the molecular structure of the third metabolite, which is dihydroxylated and appears to be the major metabolite recovered in the urine of man, has not to our knowledge been previously identified. It should be pointed out that the monohydroxylated metabolite, the major metabolite found in the dog (10), has been shown to possess uricosuric and natriuretic activity in this species(A.E.…”

Pharmacokinetic study of 2,3-dichloro 4-[2-thienyl keto14C] phenoxyacetic acid (Tienilic acid) in animals I. Localisation, distribution and elimination of14C Tienilic acid in animals

“…In addition, the biotransformation process of Tienilic acid must be taken into account for a better understanding of the metabolism of this product (9).…”

“…This paper is the first part on the pharmacokinetic study of 14C tienilic acid, the results of localization, distribution, elimination of this diuretic are given in mice, rats, pigs and dogs after oral administration. A second part, on the comparative study of the biotransformation of 14C tienilic acid in several species, will be published in a following paper (9).…”