Disposition of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in dog and rat.
The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide (DMPP), an inhibitor of acyl-CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual-labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete, amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG-400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat. DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half-life of 14C was 105 h in the dog and 83 h in the rat, while that of 3H was approximately 32 h in both species.
Tse
F L
FL
Department of Drug Metabolism, Sandoz Research Institute, East Hanover, New Jersey 07936.
Jaffe
J M
JM
D000818:Animals; D001711:Biotransformation; D004246:Dimethylphenylpiperazinium Iodide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D006207:Half-Life; D007408:Intestinal Absorption; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D010879:Piperazines; D004246:Dimethylphenylpiperazinium Iodide; D002785:Sterol O-Acyltransferase