Influence of gastric acidity on the bioavailability of digoxin.
OBJECTIVE
To study how changes in gastric acidity induced by omeprazole and pentagastrin affect the absorption of unchanged digoxin and its hydrolytic breakdown products.


METHODS
Double-blind, double-dummy, randomized, crossover study.


METHODS
Academic department of clinical pharmacology.


METHODS
Six healthy male volunteers.


METHODS
Subjects received digoxin, 1 mg orally, on three separate occasions: first, after pretreatment with omeprazole; second, after pretreatment with pentagastrin; and third, after "pretreatment" with placebo.


METHODS
The in-vitro decomposition of digoxin wa studied using a standard dissolution test. The urinary excretion of digoxin over a 120-hour period was measured using selective high-pressure liquid chromatography (HPLC) and a polarization enzyme immunoassay (EIA). Plasma concentrations were measured at 2 hours with the EIA.


RESULTS
Digoxin was rapidly released from the tablets in the in-vitro test. At acid pH, decomposition (as measured with HPLC) was rapid. Pentagastrin reduced the urinary excretion of unchanged digoxin, as measured by HPLC, from 34% to 21.4% of the dose (difference, -12.6%; 95% Cl, -23.5 to -1.8; P less than 0.05), whereas omeprazole increased urinary excretion to 47.4% (difference, 13.4%; 95 Cl, 2.5% to 24.4%; P less than 0.05). However, such differences were not found with the nonselective polarization EIA.


CONCLUSIONS
Our data suggest that gastric acidity causes the breakdown of digoxin to products that cross-react in the assay (EIA) that is commonly used clinically. In patients with reduced gastric acidity, increased plasma concentrations of unchanged digoxin may not be detected because of limitations of the EIA, which may invalidate the quantitative use of the plasma digoxin concentration as a predictor of digoxin toxicity. Omeprazole, and presumably other gastric-acid inhibitors, may increase the bioavailability of unchanged digoxin.
Cohen
A F
AF
Center for Human Drug Research, Leiden University Hospital, The Netherlands.
Kroon
R
R
Schoemaker
R
R
Hoogkamer
H
H
van Vliet
A
A
D000328:Adult; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004077:Digoxin / Q000032:analysis / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D011897:Random Allocation
D004077:Digoxin; D010418:Pentagastrin; D009853:Omeprazole