EVIDENCE FOR AN INTERACTION BETWEEN THE BETA-BLOCKER PAFENOLOL AND BILE-SALTS IN THE INTESTINAL LUMEN OF THE RAT LEADING TO DOSE-DEPENDENT ORAL ABSORPTION AND DOUBLE PEAKS IN THE PLASMA-CONCENTRATION TIME PROFILE

Pafenolol is a beta-blocker with unusual oral absorption properties. T he blood concentration-time profile exhibits two peaks, and the bioava ilability is low and dose dependent because of incomplete and nonlinea r intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lume n of rats. Further, the hypothesis that variable gastric emptying acco unts for double peaks in blood was tested by duodenal administration o f pafenolol. Following intraduodenal administration to rats with intac t bile secretion, double peaks were observed in the blood concentratio n-time curve. The bioavailability was 6.8 +/- 0.7% for the low dose (1 mumol/kg) and increased significantly to 28 +/- 10% following the hig h duodenal dose (25 mumol/kg). These blood concentration-time profiles exclude interrupted gastric emptying as cause of the twin peaks. In b ile duct-cannulated rats the intestinal absorption of the low dose (1 mumol/kg) was still poor (F = 10.7 +/-5.5%) and the blood concentratio n-time profile contained two peaks. Following administration of a high duodenal dose (25 mumol/kg) to rats with an almost bile-free small in testine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 +/- 27%. These results suggest that the low bioa vailability of pafenolol is due to a complexation between bile and paf enolol in the gut lumen, preventing intestinal uptake in the major par t of the small intestine. Further, such complex formation in the intes tinal lumen may be the underlying mechanism of the double peaks observ ed in the blood concentration-time profile.