Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil.
OBJECTIVE
To examine the secretion of the beta1-adrenergic receptor antagonist talinolol into the small intestine during its intravenous administration and to show the relevance of the P-glycoprotein-modulating drug verapamil for this secretory transport mechanism in humans.


METHODS
In six healthy volunteers the intestinal steady-state perfusion technique (triple lumen tubing system) was used for measuring the appearance of talinolol within the small intestine while the drug was infused intravenously. During four of the seven perfusions performed, the perfusion fluid was changed from a verapamil-free solution and talinolol appearance was measured while a R-verapamil-containing solution (565 micromol/L) was perfused.


RESULTS
Talinolol was transported into the intestinal lumen up to a concentration gradient between lumen and blood of about 5.5:1. While perfusing the small intestine with a verapamil-free solution, the intestinal secretion rate of talinolol ranged from 1.94 to 6.62 microg/min per 30 cm length of the intestine (median values). Perfusion of a R-verapamil-containing perfusion fluid resulted in lower secretion rates (0.59 to 3.71 microg/30 cm x min), corresponding to 29% to 56% of the values obtained without verapamil supplied intraluminally.


CONCLUSIONS
Intravenously administered talinolol is actively secreted into the human small intestine. This secretion is reduced by the intraluminal supply of the P-glycoprotein modulating drug R-verapamil. This gives further rationale for P-glycoprotein-mediated intestinal drug secretion as a cause for incomplete oral bioavailability and for drug interactions during intestinal absorption.
Gramatté
T
T
Institute of Clinical Pharmacology, Medical School, University of Technology Dresden, Germany. tgramatte@apogepha.de
Oertel
R
R
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000378:metabolism*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007262:Infusions, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000378:metabolism*; D012016:Reference Values; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*; D014838:Volunteers
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D011412:Propanolamines; D014665:Vasodilator Agents; C011550:talinolol; D014700:Verapamil