Disposition of a silicon‐containing amide, an inhibitor of acyl‐CoA: Cholesterol acyltransferase, in dog and rat

Tse, Francis L. S.; Jaffe, James M.

doi:10.1002/bdd.2510080504

Cited by 13 publications

(2 citation statements)

References 9 publications

(1 reference statement)

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“…The pharmacokinetics of DMPP, an inhibitor of acyl-CoA:cholesterol acyltransferase, was studied in dogs and rats; see Scheme . DMPP is a 3-( n -decyldimethylsilyl)propionic acid amide, and the material used was 14 C-labeled in the carbon atom of the decyl residue adjacent to the silicon atom (asterisk).…”

Section: Degradation Of Organosiloxanesmentioning

confidence: 99%

Environmental Chemistry of Organosiloxanes

2014

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Section: Degradation Of Organosiloxanesmentioning

confidence: 99%

Environmental Chemistry of Organosiloxanes

2014

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“…As mentioned in the introduction, despite showing potent efficacy in several animal models, the hypocholesterolaemic activity of ACAT inhibitors in man is not clear. In general, Plasma concentrations of ACAT inhibitors are low (Tse & Jaffe 1988;Hainer et al 1994), and ACAT inhibitors with low bioavailability and present at low concentrations in plasma had no effects on regulation of plasma lipids in man (Peck et al 1995). In a clinical study, a reduction in serum cholesterol levels was induced by a high plasma concentration of YM 17E together with active metabolites.…”

Section: Discussionmentioning

confidence: 99%

In-vitro Metabolism of YM17E, an Inhibitor of Acyl Coenzyme A: Cholesterol Acyltransferase, by Liver Microsomes in Man

Uchida¹,

Watanabe²,

Hoogdalem³

et al. 1996

Journal of Pharmacy and Pharmacology

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Because YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl) ureido]methyl]benzene dihydrochloride) inhibits acyl coenzyme A:cholesterol acyltransferase (ACAT) it has potential application in the treatment of hypercholesterolaemia. In man and animals YM17E is extensively metabolized, via N-demethylation, to five active metabolites (M1, M2-a, M2-b, M3 and M4). The main objectives of this study were to examine inhibition of YM17E metabolism by the products and identify the cytochrome P450 isoforms in liver microsomes which catalyse in-vitro YM17E metabolism in man. In microsomes in man N-demethylation of YM17E to M1 occurred enzymatically; for up to 45 s the rate was linearly proportional to the microsomal protein concentration. This reaction was inhibited by metabolites M2-a, M2-b, M3 and M4. Further, N-demethylation of [14C]-YM17E was also inhibited by its product, M1. These results showed that primary metabolism of YM17E was inhibited by its products, and supported the finding that the non-linear increase in plasma concentration of the parent drug and metabolites observed in an in-vivo study was due to inhibition by these products. Metabolic activity in microsomes from ten individual human livers demonstrated that YM17E N-demethylase activity correlated closely with testosterone 6 beta-hydroxylase activity. When cytochrome P450 isozyme-specific substrates and chemical inhibitors were used to inhibit YM17E N-demethylase activity, CYP3A-specific substrate and inhibitors such as nifedipine, ketoconazole and triacetyloleandomycin strongly inhibited this activity, whereas CYP1A-specific substrate or inhibitor, ethoxyresorufin and alpha-naphthoflavone, inhibited weakly. Other CYP inhibitors, in contrast, had few or no effects. An inhibition study using anti-rat CYP1A1, CYP2B1, CYP2C11, CYP2E1 and CYP3A2 antibodies demonstrated that only anti-rat CYP3A2 antibody inhibited YM17E metabolism, to 40% of control level, with no other antibodies showing an inhibitory effect. Of seven cDNA-expressed P450 isoforms in man (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 and CYP3A4), CYP3A4, CYP2D6 and CYP1A2 isozyme exhibited substantial catalytic activity of N-demethylation of YM17E. These results indicate the predominant role of CYP3A4 in liver metabolism of YM17E in man.

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

Tse¹,

Jaffe²

1988

Biopharm & Drug Disp

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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.

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Disposition of a silicon‐containing amide, an inhibitor of acyl‐CoA: Cholesterol acyltransferase, in dog and rat

Cited by 13 publications

References 9 publications

Environmental Chemistry of Organosiloxanes

Environmental Chemistry of Organosiloxanes

In-vitro Metabolism of YM17E, an Inhibitor of Acyl Coenzyme A: Cholesterol Acyltransferase, by Liver Microsomes in Man

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

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