Metabolism of 3-(2′,4′,5′-Triethoxybenzoyl)propionic Acid, a New Biliary Smooth Muscle Relaxant with Choleretic Activity: I. Disposition after a Single Administration in Rats and Dogs

Abstract

1. Orally administered [¹⁴C]triethoxybenzoylpropionate was absorbed from rat intestine by the portal route to give a maximum plasma level at 0.5 h and an apparent half-life of 1.7 h. In dogs, the plasma level of the drug, after oral administration, reached a plateau at 0.5 h, which persisted for 1.5 h and then declined with a half-life of 21.6 h. In both rats and dogs, the plasma ¹⁴C was predominantly due to unchanged drug, mostly bound to plasma protein.

2. After oral administration of [¹⁴C]triethoxybenzoylpropionate to rats, the tissue distribution of ¹⁴C was max. at 0.5 h with highest concn. in stomach, followed by kidney, liver, plasma and intestine, and lowest in brain. Autoradiography of pregnant rats showed that the labelled drug, after intravenous administration, crossed the placenta giving relatively higher concn. in foetal liver, blood and lung.

3. Urinary and faecal excretion of ¹⁴C after oral administration of [¹⁴C]triethoxybenzoylpropionate was 78%, dose in rats and 38% in dogs, in 24 h. Rats excreted more in urine than in faeces, while dogs excreted more in faeces. Biliary excretion of ¹⁴C in 6 h after intravenous administration was 65 and 36% dose in rats and dogs, respectively. Enterohepatic cycling of biliary ¹⁴C occurred in rats. Radioactivity was detected in the milk of rats given the labelled drug intravenously.

4. Triethoxybenzoylpropionate was metabolized preferentially to 3-(2′,4′-diethoxy-5′-hydroxybenzoyl)propionate and 3-[2′,4′-diethoxy-5′-(2-hydroxyethoxy)benzoyl]propionate in rats, whereas the formation of 3-(2′,5′-diethoxy-4′-hydroxybenzoyl)propionate was predominant in dogs. These metabolites and unchanged drug comprised >60% of urinary and biliary ¹⁴C in both animals. The metabolites, together with the intact drug, were partly conjugated with glucuronic acid and/or sulphuric acid before excretion in urine and bile.