title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Lennernäs
authors.forename: L
authors.initials: L
authors.lastname: Renberg
authors.forename: K J
authors.initials: KJ
authors.lastname: Hoffmann
authors.forename: C G
authors.initials: CG
authors.lastname: Regårdh
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C036625:pafenolol