Metabolism of the anti-obesity agent, 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride, in rats and dogs

Abstract

1. In 24 h, male rats excreted in urine 1% of an intra-gastric 100mg/kg dose of 4-amino-5-ethyl-3-[4-¹⁴C]thiophenecarboxylic acid methyl ester hydrochloride (I) as unchanged I and 59% as 4-amino-5-ethyl-3-thiophenecarboxylic acid (II), mostly conjugated.

2. In rats dosed intra-duodenally with I (50mg/kg), little I was found in the systemic circulation (< 2μg/ml) but high concentrations (26 μg/ml) were present at five minutes in portal plasma. At five minutes, II was found at 89 and 93 μg/ml in systemic and portal plasma, respectively. First-pass ester hydrolysis by the duodenum and liver may explain the near absence of I and the high concentrations of II in systemic plasma.

3. Dogs which received 30 mg/kg ¹⁴C-I intra-gastrically, excreted 0.3% I, 30.8 II and 6.8% as 5-ethyl-4-(methylamino)-3-thiophenecarboxylic acid (III), the N-methyl derivative of II.

4. Dogs which received approximately equivalent intra-venous or intra-gastric doses of non-radioactive I and II had high plasma concentrations of II but only small concentrations of I. Plasma concentrations of II after intra-gastric doses of non-radioactive I or II were similar, indicating that both compounds are pharmacokinetically equivalent. I may be a prodrug of II.