Presystemic elimination of the beta-blocker pafenolol in the rat after oral and intraperitoneal administration and identification of a main metabolite in both rats and humans
Lennernäs, H.; Renberg, L.; Hoffmann, K.J.; Regårdh, C.G.
Drug Metabolism and Disposition the Biological Fate of Chemicals 21(3): 435-440
1993
ISSN/ISBN: 0090-9556 PMID: 8100498 Document Number: 412776
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 mu-mol/kg) to 33.3 +- 5.8% (25 mu-mol/kg, p lt 0.001). This was primarily due to a change in the fraction of the absorbed dose (f-a) from 2.19 +- 4.6 to 39.5 +- 7.9% (p lt 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 apprx 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.