Influence of gastric pH on digoxin biotransformation. II. Extractable urinary metabolites

High-performance liquid chromatography (HPLC) analysis was performed on methylene chloride extracts of urine from six subjects after administration of 3H-digoxin-12 alpha and unlabeled digoxin by nasogastric tube under four conditions: pentagastrin and control saline infusions, each in the supine and ambulatory states. There were no differences with change in position. With pentagastrin stimulation of acid secretion, there was extensive intragastric hydrolysis, mainly to digoxigenin; there was further extensive biotransformation leading to an increase in both extractable and unextractable metabolites in urine, particularly the latter. In the first 5 hr mean digoxin was only 17% and unextractable metabolites were 54% of total urine radioactivity. Extractable radioactivity was found under HPLC peaks with retention times of digoxin, digoxigenin, and its mono- and bis-digitoxosides. There were also three other peaks that were not identified; two correlated with gastric H+ activity and with the peak for digoxigenin, which is probably their precursor since similar peaks were found after ingestion of digoxigenin. The third unidentified peak eluted immediately after the digoxin, with which it correlated; it may have a close structural relationship to digoxin. Gastric acid stimulation induced a major increase in the production of urinary metabolites and may prove a useful model for the study of digoxin biotransformation, which is not yet well defined.