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The new choleretic ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) is absorbed well and rapidly in rats, dogs and humans. Maximum 14C plasma concentrations are found 1-2 h after oral administration of the labelled substance to fasting animals and human volunteers. When administered to test persons after breakfast, the absorption is delayed but the absorbed amount is unaffected. Elimination of the radioactivity from the plasma occurs in two phases; 24 h after administration the radioactivity concentration has dropped to 5-8% of the maximum levels. Piprozoline is almost completely metabolized during absorption. The primary metabolic step is the enzymatic hydrolysis of the ester bond to the corresponding acid (metabolite I). At the time of maximum plasma concentration most of the plasma radioactivity corresponds to metabolite I, which also possesses choleretic activity. Approx. 65% of the radioactive dose is eliminated renally in all three species, approx. 60% being excreted within the first 24 h. Approx. 40-60% of the urinary radioactivity can be ascribed to metabolite I, both in its free form and conjugated with glucuronic acid. No unchanged substance is found in the urine. A comparison of the pharmacokinetic and metabolic behaviour of piprozoline in rats, dogs and humans showed that it was similar in all three species.

This paper describes the determination of metabolic profiles of 14C marked ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) in rat, dog and human urine and rat bile with the aid of an HPLC-radioactivity detector system following the direct injection of large quantities onto an analytical C-18 column. Metabolite 1 and two glucuronic acid conjugates of metabolite I were determined quantitatively, isolated and identified. Following HPLC separation, the specific detection of radioactivity permits the determination of metabolic profiles without prior clean-up so that unstable metabolites can also be analyzed.

Studies of hexobarbital sleeping time in rats showed that only a very high dosage of ethyl(Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Problin) (500 mg/kg) produced a weak interaction with the metabolism of hexobarbital; no signs of any induction of the oxidative enzyme system were observed until 4 days after pre-treatment with 3 X 250 mg/kg. Determinations of the in vitro activity of hepatic microsomal enzymes after several days pre-treatment of male Wistar rats with 2 X 250 mg piprozoline/kg per day showed that piprozoline has only a slight inductive effect on some of the enzymes of the oxidative system. Some of the glucuronidation reactions tested showed marked increases.