Altered metabolism may be responsible for the development of drug-induced toxicities in elderly patients who must take the cardiac glycoside digoxin daily, often for years, for congestive heart failure or supraventricular arrhythmias. Two conditions of the GI tract that occur more frequently in aging subjects, achlorhydria and bacterial overgrowth of the upper small intestine, have the potential to alter the metabolism and systemic bioavailability of digoxin, the 8th most frequently prescribed drug in the USA in 1980.
Specific aims of the proposed research include (1) testing the hypothesis that achlorhydria and hypochlorhydria cause and reduction in gastric acid-mediated hydrolysis of digoxin to sugar-hydrolyzed, active metabolites, (2) testing the hypothesis that bacterial overgrowth of the small intestine causes increased formation of inactive dihydro-metabolites known to be formed by intestinal bacteria, (3) evaluating RIA-assayed serum digoxin levels for inaccuracies in high dihydro-metabolite formers, (4) evaluating the influence of anti-infective treatment of intestinal bacterial overgrowth on digoxin metabolism and on RIA-assayed serum digoxin levels and (5) identifying the intestinal bacterial species having the capability to form dihydro-metabolites. Patients on digoxin therapy and having the pertinent GI abnormality will be sought at Ohio State Univ. Hospital and Columbus area nursing homes. Potential subjects will be tested for achlorhydria and intestinal bacterial overgrowth by definitive diagnostic techniques. Urine and feces will be collected over 4 days in participating subjects and assayed by HPLC techniques for digoxin, hydrolyzed metabolites, and dihydrodigoxin. Two small subgroups of subjects will be studied a second time, one with antibiotic treatment of bacterial overgrowth and the other with simply and high degree of dihydrometabolite formation. Serum samples from these subgroups (still on chronic digoxin) will be assayed for digoxin by two RIA procedures; one having negligible interference from dihydro-metabolites and the other having substantial interference. Results of the study will provide a quantitation of metabolic changes and a better understanding of digoxin metabolism and bioavailability in these GI diseases as well as improved clinical dosage adjustment, terapeutic monitoring of digoxin serum levels, and avoidance of digoxin-induced toxicities in elderly patients.
| Hui, J; Geraets, D R; Chandrasekaran, A et al. (1994) Digoxin disposition in elderly humans with hypochlorhydria. J Clin Pharmacol 34:734-41 |
| Shomo 2nd, R E; Chandrasekaran, A; Marshall, A G et al. (1988) Laser desorption/fourier transform ion cyclotron resonance mass spectrometry: digoxin, digitoxin, and their reduced and sugar-hydrolyzed metabolites. Biomed Environ Mass Spectrom 15:295-302 |
| Chandrasekaran, A; Robertson, L W; Reuning, R H (1987) Reductive inactivation of digitoxin by Eubacterium lentum cultures. Appl Environ Microbiol 53:901-4 |
| Shepard, T A; Hui, J; Chandrasekaran, A et al. (1986) Digoxin and metabolites in urine and feces: a fluorescence derivatization--high-performance liquid chromatographic technique. J Chromatogr 380:89-98 |
| Robertson, L W; Chandrasekaran, A; Reuning, R H et al. (1986) Reduction of digoxin to 20R-dihydrodigoxin by cultures of Eubacterium lentum. Appl Environ Microbiol 51:1300-3 |
