Comparative Drug Exsorption in the Perfused Rat Intestine

Abstract

Abstract The factors affecting drug exsorption into the gastrointestinal tract are uncertain. In this study, the intestinal clearance (CLi) of compounds which vary in their lipophilicity, serum protein binding, molecular weight and ionic charge at physiological pH, has been measured. Male Sprague-Dawley rats with ligated bile ducts were infused with the test compounds through the jugular vein. The small intestine was intubated and perfused with Tyrode solution at 20 mL h−1. The CLi of the compounds investigated (urea, polyethylene glycol, inulin, albumin, dextran, barbituric acid, salicylic acid, thiobarbital, thiopental, thioseconal, theophylline, S-disopyramide and quinidine) was determined under anaesthesia by dividing the rate of a component's appearance rate in the perfusate by its carotid arterial concentration. Serum protein binding of the compounds was determined by equilibrium dialysis. The n-octanol-water partition coefficients of the compounds were measured as indices of lipophilicity. The CLi values of dextran, albumin, inulin, polyethylene glycol and urea were 0.56, 1.03, 4.5, 4.8 and 12.0 mL h−1, respectively. The larger the molecular weight of a compound, the smaller its CLi. The molecular weight is apparently one of the major determinants of CLi. Thiobarbital, thiopental and thioseconal are compounds of similar structure with increasing lipophilicity and serum protein binding. The CLi of thiobarbital, thiopental and thioseconal was proportional to the unbound fraction in serum. The unbound clearance (CLui) of three thiobarbiturates were similar (∼ 11 mL h−1). The unbound fraction of drug in serum appears to be a factor determining their CLi. Barbituric acid and salicylic acid, two acidic compounds, showed a low CLi (< 1 mL h−1). In contrast with barbituric acid and salicylic acid, the CLi of theophylline, S-disopyramide and quinidine was much higher (> 30 mL h−1). The CLi of dextran, thiopental or S-disopyramide was not affected by altered perfusion rate. Other than molecular weight and serum protein binding, the ionic charge of compounds at physiological pH was the most significant factor affecting CLi. The lipophilicity of compounds and the perfusion rate did not seem to be important factors.