The relationship between the relative absorption and increasing oral doses of amoxycillin and bacampicillin, a prodrug of ampicillin, was studied testing the hypothesis that a saturable transport system for aminopenicillins exists in the human gut. Each drug was given in four different doses in a randomized order to 12 fasting subjects. One group of subjects was given amoxycillin in single doses of 375, 750, 1500, and 3000 mg, while the other group received bacampicillin in 400, 800, 1600, and 3200 mg doses. The highest dose was four times larger than that normally used in clinical practice. Amoxycillin, and ampicillin generated from bacampicillin, were determined in plasma and urine by modern column liquid chromatographic methods. With increasing doses of the penicillins, there was a saturable increase in peak plasma concentration, plasma AUC, and urinary recovery. The mean (+/- SD) AUC values after 750, 1500, and 3000 mg amoxycillin were 86% +/- 13%, 70% +/- 16%, and 55% +/- 14% of that expected, when the expected ratio of AUC to dose was that of the 375 mg dose, assuming nonsaturable absorption. The corresponding AUC values after 800, 1600, and 3200 mg bacampicillin were 97% +/- 17%, 89% +/- 19%, and 76% +/- 11% of that expected from the results obtained after the 400 mg dose. The importance of dose of either drug for AUC and urinary recovery was analyzed according to a function implying capacity-limited absorption. The dose-dependency was most pronounced for amoxycillin (P less than 0.001). Renal drug clearance was stable within subjects throughout the dose range. Our results support the concept of capacity-limited absorption of aminopenicillins, probably by carrier-mediated transport. However, limited solubility of the compounds, especially of bacampicillin, may be a confounding factor.