Influence of gastric pH on digoxin biotransformation. I. Intragastric hydrolysis.

3H-digoxin-12 alpha and unlabeled digoxin were administered down a nasogastric tube and digoxin, digoxyigenin and its mono- and bis-digitoxosides, and pH were assayed in gastric fluid of 6 healthy subjects at intervals for 90 min each under 4 conditions: pentagastrin infusion 6 micrograms/kg/hr with the subjects ambulatory and supine, and saline infusion ambulatory and supine. Intragastric hydrolysis occurred at roughly the same rate as reported in vitro. At 90 min, an average of 12.5% of the radioactivity that remained in the gastric fluid was recovered as digoxin for the 2 conditions when pentagastrin was infused, compared with 52.5% for th 2 conditions when saline was infused. The main glycosidic metabolite was digoxigenin and the amount correlated closely with the hydrogen ion activity in gastric fluid at 90 min (r = 0.83, p less than 0.01). Only minor differences were found between the supine and ambulatory conditions. The clinical significance of these results remains to be determined.

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.

Hydrolysis of digoxin by acid.

Predictable hydrolysis of [3H]digoxin-12alpha occurred in vitro with incubation in HCl or gastric juice. Hydrolysis varied with pH, time, temperature and agitation. Digoxin, the bis- and mono-digitoxosides of digoxigenin and digoxigenin were separated by silica gel thin-layer chromatography using chloroform-ethyl acetate-glacial acetic acid (25:25:1 v/v) and were quantitated by liquid scintillation spectrometry. Hydrolysis with incubation at 37 degrees and pH 3 for 90 min was minimal, but increased with increasing acidity until greater than 70% was hydrolysed at pH 1-2 after 30 min and greater than 96% after 90 min incubation. At pH 0-9, 87% was hydrolysed after 30 min. In vitro hydrolysis in gastric fluid was slightly less than in HCl at the same pH. A volunteer was given 150 muCi[3H]digoxin-12alpha by nasogastric tube during a pentagastrin infusion when gastric pH was 0-94. He remained on his left side and samples were aspirated at intervals and immediately neutralized. Ethanol-chloroform 50-50 (v/v) extracts of the gastric fluid aspirated after 90 min and of all the urine specimens collected for 5 days were applied to a DEAE Sephadex LH-20 column. The radioactivity appeared in a single peak as digoxigenin in the 90 min gastric aspirate and in all urine specimens. Extensive intragastric hydrolysis of digoxin may occur under conditions of maximum acid output.

Proteins of ascitic fluid in constrictive pericarditis.

A patient with chronic calcific pericarditis, hepatic congestion, and fibrosis had massive ascites with a protein concentration of 5.1 g/100 ml. This fluid was in all likelihood largely derived from hepatic interstitial fluid. The ascites-serum concentration ratio for several protein species and molecular exclusion chromatography of these fluids suggested two processes may be involved in the transfer of protein from serum to ascites, namely bulk transfer of all species and molecular sieving.

Early gastric cancer.

Early gastric cancer confined to the mucosa or submucosa, similar to that described in the Japanese literature, exists in Newfoundland, on area of North America in which gastric cancer is four times more prevalent that on the rest of the continent. If untreated, this early gastric cancer will progress to advanced disease. The clinical presentation of 10 patients suffering from cancer confined to the mucosa and submucosa of the stomach is described. The disease presents with acute or chronic bleeding or unexplained dyspepsia; no abnormality of the stomach can be seen on roentgenograms. The diagnosis may be suspected at endoscopic examination. Cytologic studies using touch preparations may be suggestive but the diagnosis should be confirmed by biopsy before operation is performed.

Endoscopic diagnosis of intestinal metaplasia in Canada and Japan.

We carried out comparative studies on chronic atrophic gastritis with accompanying intestinal metaplasia using the methylene blue dye spraying, endoscopic technique on 167 Japanese and 77 Canadian outpatients free of gross stomach disease. In both population samples (Kyoto, Japan and St. John's, Newfoundland) with increasing subject age, the fundic-pyloric (F-P) border shifted cephalad indicating atrophy of the fundic mucosal glands. Japanese subjects, however, showed greater variation in location of the F-P border. The reduction in fundic gland area with aging was followed by intestinal metaplasia, the incidence and severity of which was greater in Japanese than in Canadian outpatients. From these data we conclude that a difference in the gastric mucosa in these two countries may be related to the pathogenesis of gastric cancer.