Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein.
OBJECTIVE
Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein.


METHODS
Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively.


RESULTS
Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration.


CONCLUSIONS
We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.
Westphal
K
K
Division of Clinical Pharmacology, Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
Weinbrenner
A
A
Giessmann
T
T
Stuhr
M
M
Franke
G
G
Zschiesche
M
M
Oertel
R
R
Terhaag
B
B
Kroemer
H K
HK
Siegmund
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004077:Digoxin / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D012016:Reference Values; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D011412:Propanolamines; C011550:talinolol; D004077:Digoxin