The Metabolism of Carbenoxolone in the Rat

Abstract

1. [³H]18β-Glycyrrhetic acid administered orally to rats is absorbed from the stomach and excreted in the bile as glycyrrhetyl-30-glucuronide, glycyrrhetic acid-3-O-hydrogen sulphate and a second glucuronide conjugate, probably glycyrrhetic acid 3-O-glucuronide. 18β-Glycyrrhetic acid undergoes entero-hepatic circulation in the rat.

2. Carbenoxolone labelled with ¹⁴C in the succinate moiety administered orally to intact rats gives 71% dose as ¹⁴CO₂, 26% in the faeces and 2% in the urine, and intraperitoneally gives 68% as ¹⁴CO₂. When administered to rats with biliary cannulae, oral dosage gave: 53% ₁₄CO₂, 25% in bile, 6% in faeces and 2% in urine; intraperitoneal dosage gave: 12% ¹⁴CO₂, 54% in bile, 2% in urine and none in faeces. These figures suggest that hydrolysis of [¹⁴C] carbenoxolone into [¹⁴C]succinate plus 18β-glycyrrhetic acid occurs in the gastrointestinal tract before absorption, the [¹⁴C]succinate being further metabolized to ¹⁴CO₂.

3. After oral dosage with [¹⁴C]carbenoxolone the bile contains principally the three metabolites of 18β-glycyrrhetic acid, whereas after intraperitoneal dosage the bile contains mainly a glucuronide conjugate of carbenoxolone probably carbenoxolone 30-glucuronide. There was no evidence of reduction of the 11-oxo-12-ene grouping in any of the metabolites.

4. Carbenoxolone is not hydrolysed to 18β-glycyrrhetic acid and succinic acid on incubation with rat liver homogenate, rat blood or human blood, but was hydrolysed on incubation with rat caecal contents or stomach contents.

5. It is concluded that in the rat, [¹⁴C]carbenoxolone is largely hydrolysed into [¹⁴C]succinate and 18β-glycyrrhetic acid by the active microflora present in the stomach, before absorption.