The Metabolic Fate of the Coronary Vasodilator 4-(3,4,5-Trimethoxycinnamoyl)-l-(N-pyrrolidino-carbonylmethyl)piperazine (Cinepazide) in the Rat, Dog and Man

Abstract

1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[¹⁴C]cin-namoyl)-l-(iV-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile.

2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t_o.5 < 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 : 30 : 1.

3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-l-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).