Ethyl p-Chlorophenoxyisobutyrate Clofibrate, Atromid-S

Clofibrate is a widely used hypolipidemic agent whose mode of action, like that of nicotinic acid, has not been unequivocally established (21). In the earliest studies of the effect of this compound on fecal steroid excretion (22), it was concluded that excretion of sterols was increased but that of bile acids was not. The ratio of glycocholanic/taurocholanic acid was unaffected (23). Grundy et al. (24) reported that this drug reduced fecal bile acid excretion in their patients. 

Clofibrate appears to have little general effect on bile acid metabolism, but, as Horlick et al. (25) have shown, it may affect bile acid excretion in certain types of hyperlipidemias. 

Cholestyramine is a high molecular weight anionic exchange resin which, as the chloride salt, is used to absorb bile acids. In the dog (26), this material, when fed at the level of 25 g/day, was shown to increase fecal sterols by 85 % and fecal bile acids by 160% and to reduce cholesterol levels by 22%. Rate fed 2 % of cholestyramine in the diet showed a three- to fourfold increase in bile acid excretion, and the increase was all in the dihydroxycholanic acid fraction (27). In mice (28), this resin decreased the time for bile acid turnover from 5 to 1.25 days. Fecal neutral sterols were increased by 37%. Pigs fed 2-4% cholestyramine showed a marked increase in bile acid excretion (29). 

Mosbach et al, (35) have used cholestyramine to confirm that the la-hydroxylation of cholesterol is the rate-limiting step in bile acid synthesis. Because of the loss of cholesterol from the enterohepatic circulation, there is a marked increase in cholesterol synthesis during administration of cholestyramine to rats (27) or man (36). Mosbach et aL, using perfused rabbit liver, showed that the biliary content of glycocholic acid rose from 0.34 to 3.3 mg, while the content of glycodeoxycholic acid fell from 7.4 to 3.7 mg. The conversion of radioactive acetate, mevalonate, or cholesterol to bile acids was increased from five- to twentyfold, but the conversion rate of 7a-hy-droxycholesterol to cholic acid was unchanged. The formation of 7a-hy-droxycholesterol from cholesterol is enhanced by treatment with cholestyramine (37,38). 

Other resins (39) have been shown to bind bile acids and to lower cholesterol levels by inhibiting its reabsorption however, it is apparent that these compounds exert a specific effect on bile acid metabolism. 

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