Pharmacokinetics and metabolism of the antiarrhythmic agent [3H]-diprafenone in the rat.
After acute intravenous (i.v.) administration of 3 mg/kg of 3H-labelled 2'[2-hydroxy-3-(1,1-dimethylpropylamino)propoxy]-3-phenylproiop henon hydrochloride ([3H]-diprafenone), plasma radioactivity levels declined biphasically with half-lives of 0.2 h (alpha-phase) and 1.5 h (beta-phase), respectively. After acute oral administration of 9 mg/kg, absorption was prompt but continued, similar to a zero-order process, over many hours resulting in plateau-like plasma levels up to 5-6 h and a subsequent slow decline with a beta-half-life of 6-8 h. Absorption varied between 50 and 80%. Distribution of [3H]-diprafenone was rapid and tissue levels in general paralleled blood levels. After i.v. dosing highest levels of radioactivity were found in the lung; after oral application in the gastrointestinal tract. Radioactivity was distributed into subcellular organelles and the cytosol resulting in an apparent volume of distribution (Varea) of 4-5 l/kg. About 95% of the 3H-activity given was excreted in urine (20%) and faeces (75%) within 48 h after i.v. administration. After oral application, total 3H-recovery was substantially lower. After i.v. dosing most of the 3H-label found in faeces originated from biliary excretion and was almost completed within 4 h after administration. After oral application, biliary excretion varied between about 5 and 35% indicating protracted absorption. 3H-radioactivity was reabsorbed and subject to extensive enterohepatic cycling. After repetitive oral administration, total radioactivity reached a steady state after 4-5 days. The corresponding cumulation factors R ranged between 2 and 3. A decline in elimination rate is likely. [3H]-Diprafenone was metabolized rapidly and quantitatively.(ABSTRACT TRUNCATED AT 250 WORDS)
Brunner
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F
Department of Pharmacodynamics and Toxicology, Faculty of Sciences, University of Graz, Austria.
Kolmayr
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U
Kukovetz
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WR
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005260:Female; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D011405:Propafenone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D001798:Blood Proteins; C047546:diprafenone; D011405:Propafenone