Pafenolol is a beta 1-adrenoreceptor antagonist exhibiting some interesting oral absorption properties in both rat and humans. The blood concentration-time profile exhibits two peaks, and the bioavailability is low and dose-dependent due to an incomplete and nonlinear intestinal uptake. The origin of the presystemic metabolism was studied in rats after oral and intraperitoneal administration of tritium-labeled pafenolol with reference to the intravenous route by means of urinary excretion data of pafenolol and metabolites specifically assayed by HPLC and radioisotope detection. The oral-bioavailability increased from 15.8 +/- 4.1% (1.0 mumol/kg) to 33.3 +/- 5.8% (25 mumol/kg, p < 0.001). This was primarily due to a change in the fraction of the absorbed dose (fa) from 21.9 +/- 4.6 to 39.5 +/- 7.9% (p < 0.01). The bioavailability following an intraperitoneal dose was almost complete indicating that the presystemic metabolism was due to gut wall metabolism. Saturation of the presystemic metabolism contributed only by approximately 15-20% to the 2-fold increase of bioavailability. This clearly indicates that the underlying mechanism for the low and dose-dependent bioavailability was an incomplete and nonlinear intestinal uptake. The metabolic pattern showed that at least eight metabolites are formed in the rat. One of these is an alpha-OH pafenolol, identified as the main metabolite in human urine by mass spectrometry.