Sulfisoxazole acetyl, riboflavin, tetracycline and bretylium were administered both orally and intravenously to senescent (28–40 months) and mature (12–19 months) male Sprague-Dawley rats. The extent of drug absorption was calculated from the urinary recovery of each drug after oral administration relative to its recovery after intravenous administration. The recovery of the four drugs after intravenous administration was similar in both groups, although urinary excretion of sulfisoxazole acetyl and tetracycline was relatively slow in the senescent animals and there was a tendency for recovery of less riboflavin and more bretylium compared to the mature rats. A comparison of the extents of absorption of the four drugs showed no differences (p < 0.05) between the senescent and mature groups, with n = 6–9 animals per group. The data were quite variable and there was a tendency for decreased absorption of tetracycline (p = 0.28) and increased absorption of bretylium (p = 0.08) in the senescent compared to the mature animals. The rate of absorption of bretylium, tetracycline, and sulfisoxazole acetyl was measured in senescent (age 31 months) and mature (age 16 months) rats, by determining the amount of each drug that remained in the GI tract at 40, 80, and 160 min after its oral administration. During the initial 40 min after dosing, the rate of absorption of the drugs was similar in senescent and mature rats because the gastric emptying rates were similar in both groups. Between 40 and 160 min after dosing, the absorption rates of bretylium and sulfisoxazole acetyl tended to increase in senescent compared to mature animals while the absorption rate of tetracycline tended to decline. The permeability of the in situ intestinal epithelium to sulfisoxazole acetyl and bretylium was determined by recirculating solutions of the drugs through segments of the small intestine, and measuring the rate of decline of the drug concentration. The permeability of the jejunal epithelium to the sulfonamide was similar in both groups, but the jejunal permeability to bretylium was lower in senescent than in mature animals. When the perfused segment included the ileum, the permeability to bretylium was similar in both groups.