Background: Glutathione (GSH) and the cytosolic glutathione S-transferases (GSTs) protect the gastrointestinal mucosa against the toxic effects of a wide variety of compounds, such as reactive oxygen species and electrophiles. Aims: We wished to investigate the distribution along the upper gastrointestinal mucosa and the influence of clinical variables on components of the GSH system to learn more about factors which control its cytoprotective properties. Methods: Antral and duodenal biopsies of normal appearing mucosa were collected from 202 patients (104 males, 98 females; mean age 62 years) undergoing upper gastrointestinal endoscopy. GSH content was examined by high pressure liquid chromatography, GST enzyme activity by 1-chloro-, 2, 4-dinitrobenzene conjugation, and levels of the GST classes alpha, pi, and theta by western blot. Results: GSH, GST enzyme activity, and GST alpha levels were significantly lower (p<0.001) in the antrum than in the duodenum (antrum v duodenum: GSH 23.0 (0.7) v 35.0 (1.0) nmol/mg protein; GST activity 626 (19) v 832 (22) nmol/mg protein/min; GST alpha 4.5 (0.5) v 20.0 (0.7) µg/mg protein) while GST pi content was significantly higher (p<0.001) in antral than in duodenal biopsies (16.5 (0.7) v 11.2 (0.5) µg/mg protein). Antral GSH and GST activities were markedly lower in males compared with females (p<0.01). Some drugs (cisapride, diuretics, cortisol, analgesics) increased GST pi and GST alpha content but cytostatic drugs suppressed duodenal GST activity. High intake (>3 days a week) of vegetables enhanced duodenal GST alpha and GST pi and high intake of fruits the antral content of GST theta1. Conclusions: The gastrointestinal GSH system represents the antitoxic barrier of the mucosa; its activity is influenced by localisation, sex, and drugs, and its enzymes are stimulated by a high intake of vegetables and fruits.

Although the influence of thyroid dysfunction on the effectiveness and disposition of drugs has been extensively studied, the pharmacokinetic/pharmacodynamic interactions between cardiac glycosides and antithyroid drugs have not been investigated. This possibility arose following the clinical observation of relatively lower digoxin plasma levels in 1 patient concomitantly treated with Carbimazole. We therefore examined the influence of a single oral dose of 60mg Carbimazole or placebo on the steady-state serum levels and haemodynamic effects of digoxin (0.375mg maintenance dose) in 10 healthy subjects according to a double-blind randomised crossover design. Serum digoxin levels were measured by the fluorescence polarisation immunoassay technique; haemodynamic parameters, cardiac output and stroke volume were determined by Doppler echo-aortography. Peak serum levels (Cmax) of digoxin were significantly lowered (1.72 ± 0.33 vs 1.33 ± 0.29 µtg/L, p = 0.0275) in 9 out of 10 subjects when digoxin was combined with Carbimazole. The mean time to reach peak levels (tmax) and area under the serum concentration-time curve (AUC0-24) were not significantly affected. However, serum digoxin levels rose considerably in 1 subject upon administration of Carbimazole (Cmax 1.08 to 2.38 µg/L and AUC0-24 12.75 to 23.85 µg/L·h). Systolic blood pressure was significantly lowered (p < 0.05) for 3 hours with digoxin alone, but not when Carbimazole was added. Diastolic blood pressure was also significantly (p < 0.05) reduced up to 12 hours with digoxin, but for for 6 hours with combination treatment. Despite the fact that the investigated drugs are structurally and functionally unrelated, these results suggest the need to monitor digoxin plasma levels when concomitantly administering antithyroid drugs.

A 65-year-old woman, known to have peptic ulcers, developed nausea and retching. Clinical examination demonstrated pain on pressure in the epigastrium with otherwise normative findings for age. Two gastric ulcers and gastritis with erosions were seen at endoscopy. The patient, who was being treated with digitoxin for heart failure, reported having taken up to four digitoxin tablets (0.07 mg each) daily because she had insomnia. The plasma digitoxin level was between 150 and 160 nmol/l (therapeutic range 17-33 nmol/l), while the ECG showed no signs of digitalis intoxication. Initially the platelet count was 40,000/microliter: there had been no history of thrombocytopenia or symptoms of abnormal haemostasis. Other laboratory tests were within normal limits. After digitoxin had been discontinued, the platelet count rose without further treatment to 373,000/microliter 3 weeks after hospital admission by which time the digitoxin level had fallen to 48.9 nmol/l. The gastrointestinal symptoms regressed completely on treatment with omeprazole (40 mg three times daily for 8 days) and ranitidine (150 mg twice daily).