DIRECT DEMONSTRATION OF SMALL-INTESTINAL SECRETION AND SITE-DEPENDENTABSORPTION OF THE BETA-BLOCKER TALINOLOL IN HUMANS

Objective: To examine the relevance of site-dependent small intestinal absorption for incomplete intestinal absorption of the poorly metabol ized beta(1)-adrenergic receptor antagonist talinolol. Methods: The in testinal steady-state perfusion technique (triple lumen tubing system with a 30 cm test segment) for intraluminal measurements was combined with simultaneous determination of talinolol serum concentrations, Dis solved talinolol was perfused over 160 minutes into different parts of the small intestine, The middle of the test segment was located betwe en 95 and 235 cm beyond the teeth, Each of the six healthy subjects wa s studied twice with a proximal and a more distal site of perfusion to allow for comparisons within an individual subject. Results: The area under the curve for serum concentrations from 0 to 480 minutes [AUC(0 -480 min)] and the maximum serum concentration after distal perfusions corresponded to only 15% to 73% and 7% to 90% of the proximal values, respectively. AUC decreased with increasing distance from the teeth, The mean amount of talinolol absorbed from the test segment per unit t ime (intestinal transport rate) corresponds to only one-tenth of the a mount of drug offered to the test segment (perfusion rate), There was a direct correlation between the perfusion rate of talinolol and its t ransport rate for both regions and in all subjects investigated, Howev er, to achieve the same transport rate in the distal region a higher p erfusion rate is required, compared to the proximal small intestine, A t perfusion rates lower than 600 mu g/min, net secretion of talinolol into the intestinal lumen occurred against a steep concentration gradi ent blood: lumen of about 1:4200. Conclusion: Talinolol oral bioavaila bility of 55% is due to a low absorption rate and a decrease of absorp tion capabilities along the small intestine, Net absorption of talinol ol is reduced by the involvement of active intestinal secretion.