Comparative studies on the disposition of two pairs of drugs and their prodrugs, i.e., (1) salicylamide (SAM) and ethenzamide (ETB), (2) acetaminophen (NAPA) and phenacetin (PHT), were performed in dogs following intravenous and oral administration of the drugs. ETB and PHT were largely metabolized to SAM and NAPA, respectively, and SAM and NAPA thus formed or those directly administered were conjugated with sulfuric acid and glucuronic acid. It was found that the prodrugs, ETB and PHT, were more susceptible to first-pass metabolism than the corresponding parent drugs, SAM and NAPA, respectively at 30 mg/kg dose of each drug. Free NAPA levels in the blood of dogs receiving PHT were found to be considerably high, whereas free SAM levels in the blood of dogs receiving ETB were very low. These are consistent with results in humans which have been reported earlier, suggesting the similarity between dogs and humans. The ratio of sulfate to the sum of sulfate and glucuronide (S-ratio) as the area under blood concentration-time curve and urine were examined. The prodrugs (ETB and PHT) showed higher S-ratios than the corresponding parent drugs (SAM and NAPA). The S-ratios were greater than 0.6 in ETB and SAM and less than 0.5 in PHT and NAPA, indicating that sulfate formation was predominant in the former pair while glucuronide formation was predominant in the latter pair. No intestinal metabolism was found in the prodrugs. In the parent drugs, however, conjugation with sulfuric acid and glucuronic acid was observed.(ABSTRACT TRUNCATED AT 250 WORDS)