AlPO4is generally perceived as a particularly weak antacid. Its neutralizing capacity, when evaluated with the classical Fordtran test at the pH 3 standard, is several times smaller than that of Al(OH)3, which is considered a particularly potent antacid. This difference of in vitro reactivity of the two antacids is largely due to the fact that the pKa value is considerably lower for AlPO4than for Al(OH)3. The object of this study was to evaluate in vivo and in vitro the impact of the pKa value of these antacids on their efficacy at low pH values and the modulation of their neutralizing capacity through proteins. Since both preparations display a much closer antacid activity at pH 2, we felt it appropriate to reevaluate the comparative in vivo neutralizing capacity of the two antacids at doses matched with their in vitro reactivity at pH 2. In vivo antacid effects were measured by ambulant pH-metry in 18 healthy volunteers after randomized ingestion of carbohydrate or protein meals. Antacid or placebo medication was given 1 and 3 h after meals. At pH 3.0, the standard milieu of the Fordtran test, preparation A, composed of Al(OH)3and a small fraction of Mg(OH)2, displayed in vitro a neutralizing capacity of 4.4 mmol/ml, whereas this was 0.18 mmol/ml for preparation B, composed solely of AlPO4)(p<0.001). When tested at pH 1,1.5, and 2, however, the ratio between A and B was below 2. The results of the in vivo studies confirmed our working hypothesis that neutralizing capacity at pH 2 is a better predictor of the in vivo antacid potency of AlPO4and Al(OH)3, since, in the 14-h pH-metry study, repeated applications of each antacid led to a similar shift of intragastric pH. Moreover, we found that each antacid neutralized intragastric acidity more effectively when the protein meal was administered in the afternoon instead of in the morning, despite a strong and more protracted stimulation of acid secretion after the afternoon protein meal. This suggests that timing, in addition to composition of a meal, determines in vivo reactivity of antacids.