Age-related changes in gastric function will be studied and related to absorption of orally administered drugs. Gastric achlorhydria and delayed emptying are believed to be more common in the elderly. Two hundred and forty men and women aged 65 and older will be screened to ascertain prevalence and characteristics of those with achlorhydria. Serum pepsinogen and gastrin levels will be used as indicators of atrophic gastritis, and inability to secrete acid. Another non-invasive test for acid entails swallowing water containing a carboxylic cation exchange resin to which a marker, such as quinine, is bound. Gastric acid displaces the quinine, which is then absorbed and excreted in the urine. Absence of urinary quinine denotes achlorhydria. This resin test has been validated in young adults with normal secretory status and after suppression of acid by the H2 receptor antagonist, famotidine. Gastric pH will be confirmed directly by concomitant ingestion of a radiotelemetry pH capsule. Subjects will also be screened for intestinal bacterial overgrowth by breath hydrogen excretion after glucose ingestion. In the second year, studies will begin of gastrointestinal absorption of the anti-infective agents, enoxacin and ketoconazole. The solubility of both drugs is markedly reduced at pH above 5 and their absorption is depressed by achlorhydria induced by cimetidine or ranitidine. Both drugs are quite safe and their pharmacokinetics have been well defined in man. Enoxacin, 400 mg, will be administered in tablets and solution to twelve elderly (aged 65 and over) acid secretors and twelve nonsecretors identified by prior screening. They will also receive an intravenous infusion of enoxacin to determine absolute bioavailability. 99mTc DTPA, 100 muCi, will be swallowed at the same time as oral enoxacin to determine emptying of the stomach by external gamma camera.. Gastric pH will be measured with a radiotelemetry capsule. Passage of this nonabsorbable object out of the stomach will be indicated by a pH shift. Blood and urine levels of enoxacin, measured by HPLC, will be analyzed by AUC, Cmax and tmax to compare absorption in acid secretors and non-secretors. After completion of enoxacin studies, or if this drug does not become available in time for study, ketoconazole absorption will be similarly investigated in elderly acid secretors and non-secretors. Ketoconazole, 200 mg in tablets or dissolved in 0.1N HC1 plus orange juice, will be swallowed with 99mTc DTPA and a radiotelemetry pH capsule as described. Ketoconazole levels in blood will be assayed by HPLC and analyzed to compare absorption in aged achlorhydrics and acid secretors. Only if there is no difference in absorption of either drug between acid secretors and non-secretors will the effect of famotidine, an H2 receptor antagonist, on drug absorption be studied. These studies will define the prevalence of age-related changes in gastric function and their effects on bioavailability of two clinically relevant model drugs. Extension of such studies to other classes of drugs will make possible rational prediction of altered drug bioavailability in the elderly.
