Hypolipidemic active metabolites

Sewage water was extracted under acidic, neutral, and basic conditions with methylene chloride and these extracts, both free and methylated, were screened by gas chromatography-mass spectrometry. The presence of 2-(4-chlorophenoxy)-2-methylpropanoic acid (CPIB), the active metabolite of the widely used hypolipidemic drug, clofibrate, and 2-hydroxy benzoic acid (salicyclic acid), a metabolite of aspirin, was established in these screens. This is to our knowledge the first report of detection of drugs in water samples. A review describing the detection of other organic compounds has recently appeared (1). 

Metabolites (14a), (14b), and (14c) have hypoglycemic and hypolipidemic effects in Wistar fatty rats, and may contribute significantly to the pharmacological activity of pioglitazone in humans. Serum half-life of the parent drug is 3-7 h, whereas that for total pioglitazone-related species is 16-24 h. From 15 to 30% of an oral dose is excreted in the urine, primarily as metabolites and their conjugates. The balance is presumably excreted in the bile. 

Differences in Ligand Inducibility. Hiunan PPARa is not more sensitive than rodent PPARa to chemical activation. Most compounds activate the rodent receptor better or exhibit no differences between species. A munber of environmentally relevant chemicals and hypolipidemic agents were able to activate rat or mouse PPARa at lower concentrations or to higher absolute levels than hPPARa in side-by-side trans-activation studies. These PPARa activators include WY-14,643 (Keller et al. 1997 Maloney and Waxman 1999 Takacs and Abbott 2007), PFOA (Maloney and Waxman 1999), perfluorooctanesulfonate (Shipley et al. 2004 Takacs and Abbott 2007), and a number of phthalate ester metabolites [Bility et al. (2004) and summarized in Corton and Lapinskas (2005)]. Some PPARa activators show no differences between activation of the mouse and hiunan PPARa, including TCA, dichloroacetate, 2-ethylhexanoic acid (Maloney and Waxman 1999), a number of phthalates (Bility et al. 2004), clofibrate (Keller et al. 1993), and PFOA (Vanden Heuvel et al. 2006). Only perfluorooctanesulfonamide (Shipley et al. 2004) was shown to modestly activate the human but not the rodent PPARa at one lower dose (25 jM in human versus 34 pM mouse). Overall, the data indicate that hPPARa is no more sensitive than the mouse or rat PPARa to significant activation by environmentally relevant PPARa activators. 

An important class of active agents that potently inhibit HMG-CoA reductase has evolved from extensive studies for microbial secondary metabolites. Since Brown and Goldstein have reported that the rate of cholesterol biosynthesis is determined by the activity of HMG-CoA reductase [19,20,21], this enzyme has been known to be a prime target for discovery of novel therapeutics against hypercholesterolemia. Several fimgal secondary metabolites were isolated as useful inhibitors of endogenous cholesterol biosynthesis and developed as commercially available hypolipidemics. Endo and Hasumi have extensively reviewed natural, semisynthetic and synthetic HMG-CoA reductase inhibitors in 1993 [22],... 

Aarsland, A., Berge, R.K., Bremer, J. Aarsaether, N. 1990. Biochim. Biophys. Acta 1033 176-183. The hypolipidemic peroxisome-proliferating drug, bis(carboxymethylthio)-110 decane, a dicarboxylic metabolite of tiadenol, is activated to an acylenzyme A thioester. 

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