Abstract
A pH-profile of the absorption of [[14]C] carbenoxolone from the rat small intestine, both in vivo and in vitro, demonstrated that optimal absorption occurred from alkaline solutions. The pattern of carbenoxolone absorption was related to its water solubility, and the absorption of the ionised form of the drug. The gastric absorption of [[14]C]carbenoxolone was negligible when compared to the intestinal absorption, and it was therefore inferred that the major site of absorption of this drug is the intestine. An intravenous dose of [[14]C] carbenoxolone initially distributed into an apparent volume of 5% of body weight, and had a plasma half-life of 15 minutes. A tissue distribution study of [[14]C] carbenoxolone showed that it was confined largely to the gastrointestinal tract, liver and blood plasma. The protein binding characteristics of the drug were of greater importance than its lipid solubility in determining its tissue distribution. After parenteral administration of [[14]C] carbenoxolone to rats, some of the. radioactive drug and conjugates migrate back into the gastrointestinal tract, in particular to the gastric mucosa. The interaction of carbenoxolone with endogenous corticosteroids was investigated by studying the transport, metabolism, excretion and tissue binding of [3H] corticosterone and Ph] aldosterone in the rat. Acute carbenoxolone treatment significantly reduced (50%) the biliary excretion rate of [[3H]] aldosterone, [[3]H]corticosterone and their metabolites. Carbenoxolone pretreatment increased the plasma half-life of [[3]H] aldosterone, and reduced the amount of radioactive metabolites in the intestinal mucosa. The effect of carbenoxolone on the renal binding of [[3]H] aldosterone was studied both in vivo and in vitro. In control rats,saturation of nuclear binding occurred at a plasma aldosterone concentration of 0. 83 nM, whereas carbenoxolone treatment decreased this value to 0. 52 nM. Carbenoxolone displaced [[3]H] aldosterone in vitro from some nuclear binding sites, but not from the stereospecific mineralocorticoid-binding macromolecules isolated from kidney nuclei.