SHORT-TERM EFFECTS OF SIMVASTATIN ON BILE-ACID SYNTHESIS AND BILE LIPID SECRETION IN HUMAN-SUBJECTS

To test whether de novo synthesis of cholesterol is limiting factor fo r bile acid synthesis, we studied th acute effect of simvastatin, an i nhibitor of HMG coenzyme A reductase (the limiting step of cholesterol synthesis) on bile acid synthesis and biliary lipid secretion in subj ects with interrupted enterohepatic circulation. In these conditions b ile acid synthesis is derepressed and is assumed to equal biliary bile acid secretion. Five cholecystectomized patients fitted with T-tubes were studied. All subjects were administered simvastatin (80 mg as a s ingle dose) 5 days after surgery. Bile was collected in 3-hr intervals for 15 hr before and 30 hr after the administration of the drug. Duri ng the experiment we kept the enterohepatic circulation of bile acid i nterrupted by inflating an occludable balloon inserted, during cholecy stectomy, in the common bile duct. Simvastatin induced significant dec reases of plasma total and low density lipoprotein cholesterol concent rations, from 163 @ 29 mg/dl and 97 +/- 24 mg/dl of the pretreatment v alue to 144 +/- 30 mg/dl and 82 +/- 22 mg/dl 18 hr after simvastatin a dministration, respectively. Bile flow tended to increase after simvas tatin, and the mean values from the third to the 15th hour after simva statin administration (22.1 +/- 1.9 ml/hr) were significantly greater than the mean values of the pretreatment period (19.9 +/- 2.8 ml/hr). Concomitantly biliary bile acid, cholesterol and phospholipid concentr ations fell from basal values of 15.9 +/- 5.1, 2.3 +/- 0.3 and 5.5 +/- 0.3 mmol/L to mean values, after treatment, of 9.0 +/- 3.5, 1.9 +/- 0 .5 and 3.0 +/- 0.9 mmol/L, respectively. Cholesterol saturation index increased from a mean value of 1.51 +/- 0.31 in the pretreatment perio d to 1.98 +/- 0.52 after simvastatin. Bile acid output decreased from a mean pretreatment value of 308.0 +/- 79.1 mumol/hr to 191.9 +/- 69.2 mumol/hr after simvastatin administration. Secretion rates of phospho lipids decreased to a lesser extent, whereas cholesterol output remain ed constant. No correlation was found between bile acid output and bil e flow, phospholipid secretion and cholesterol secretion. A significan t correlation was present between phospholipid and cholesterol secreti on. Our data show that, in conditions of derepressed bile acid synthes is, acute inhibition of HMG-coenzyme A reductase activity induces decr eased bile acid synthesis and excretion. Our findings may suggest that the availability of newly synthesized cholesterol is a critical facto r for bile acid synthesis and secretion but not for cholesterol secret ion; alternatively HMG-coenzyme A reductase and cholesterol 7alpha;-hy droxylase, the rate-limiting step of bile acid synthesis, may be coord inately regulated at the transcriptional level.