The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (≥65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HC1 (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of 99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased Cmax and AUC(0–36) exhibited in achlorhydric subjects without pretreatment. Tmax and ka were slower in achlorhydrics, although pretreatment with glutamic acid HC1 tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to >5 in all subjects and maintained it at >5 for at least 3 hr in all subjects tested. The lack of differences in Cmax and AUC(0–36) with significant differences in Tmax and ka indicated that control subjects after treatment with famotidine may serve as an adequate model for achlorhydrics with respect to the extent of absorption, but not with respect to the rate of absorption. Gastric emptying of a nutrient liquid was significantly slower in achlorhydric subjects than in control subjects. Finally, fasting serum gastrin appeared to be a relatively reliable and easy method for screening for achlorhydria in the elderly.