Abstract
Carbenoxolone has been labelled with [14]C and [3]H. [[14]C]Carbenoxolone administered as a positioned-release capsule to duodenal ulcer patients was shown to be readily absorbed. The fate of [[14]C]- and [[3]H]carbenoxolone administered orally to human volunteers has been investigated. Most of the dose was recovered as carbenoxolone in the faeces, although a portion (< 15%) was present as carbenoxolone-30-glucuronide. Peak plasma concentrations indicated at least 50% absorption of the dose. Less than 10% of the dose underwent hydrolysis to enoxolone and succinate, in contrast to the rat where extensive hydrolysis occurred after oral administration. [1,4-[14]C[2]] Succinate was rapidly and almost completely metabolised to respiratory [14]CO[2] in a human volunteer. No significant hydrolysis of [[14]C]carbenoxolone occurred after administration to intact or biliary-cannulated squirrel monkeys. Carbenoxolone was excreted in the bile mainly as carbenoxolone-30-glucuronid Conjugation appeared to be a pre-requisite for biliary excretion and conjugates were excreted against a concentration gradient. A species difference in metabolism between primates (man and squirrel monkey) and the rat was attributed to the gastrointestinal microflora. Carbenoxolone has been found to be highly bound to the plasma proteins of man and common laboratory species. The binding was investigated by a variety of methods to obtain quantitative and qualitative data on the interaction. Albumin had a very high affinity (k > 10[7]) for carbenoxolone and was found to be the principal binding protein in human plasma, although binding to globulins also occurred; carbenoxolone also induced a conformational change in the albumin. The distribution of [[14]C]carbenoxolone in the rat showed that it was confined largely to the gastrointestinal tract, liver and plasma. Pretreatment of rats with carbenoxolone had no significant effect on various hepatic microsomal enzymes concerned with the metabolism of drugs and steroids. Neither did such pretreatment influence the biliary and urinary excretion of [[3]H] cortisol and its metabolites.