Influence of high‐fat meal on the absorption of a silicon — containing amide, an inhibitor of acyl — coa: Cholesterol acyltransferase, in man

Abstract

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1- phenylethyl] propanamide (DMPP), an inhibitor of acyl-CoA: cholesterol acyltransferase, have been examined in 18 healthy male volunteers who received an oral dose of either 14C-DMPP or 3H-DMPP immediately following a high-fat meal, or 3H-DMPP in the fasting state. DMPP was poorly absorbed in the fasting subjects. Administration with a high-fat meal significantly increased the extent of absorption to 15 per cent of the dose. Simultaneous fitting of the blood levels and excretion data to a pharmacokinetic model showed that ca. 64 per cent of the absorbed DMPP was metabolized while the remainder was excreted intact via the bile. The routes of biotransformation included hydrolysis of the amide bond and oxidation of the phenyl ring. The apparent volumes of distribution for DMPP and its 14C and 3H labelled metabolites were 0.89, 0.95, and 1.6 lkg-1, respectively, suggesting that these materials were distributed into extravascular spaces. The metabolites of DMPP were partially excreted in urine, accounting for 1.2 per cent and 3.8 per cent of the postprandial 14C and 3H labelled doses, respectively. The elimination half-lives of DMPP and its 14C and 3H labelled metabolites were 2.8, 5.3, and 6.9 h, respectively.

Environmental Chemistry of Organosiloxanes

“…A follow-up study of the same compound in man resulted in negligible amounts of 14 CO 2 in exhaled air (0.2% of dose) after oral dosing . However, in a later study, tritium-labeled DMPP was orally administered to human volunteers; most of the material (92% of dose) was excreted unchanged, but the major urinary metabolite (4% of dose) was isolated and identified, and the pathway involved was reported to be “oxidation and loss of the decyl side chain to give the silanol”. , Thus, Si–C cleavage is prominent in metabolism of this compound in humans.…”