CHANGES IN BILIARY LIPID OUTPUT AFTER INTERRUPTION OF PRAVASTATIN TREATMENT IN HUMANS

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase i nhibitors (e.g. pravastatin) has gradually increased in the treatment of hypercholesterolaemia. By inhibiting HMG-CoA reductase (the rate-li miting enzyme in cholesterol synthesis) activity, cholesterol synthesi s in the Liver is reduced and the plasma level of cholesterol, especia lly low-density lipoprotein (LDL)-cholesterol, is substantially lowere d. Simultaneously, inhibition of HMG CoA reductase activity is associa ted with increased synthesis and accumulation of larger amounts of HMG CoA reductase enzyme protein. The main purpose of this study was to d etermine if the cessation of pravastatin treatment causes a rapid incr ease in the synthesis and biliary secretion of cholesterol, a conditio n which might lead to a temporarily increased cholesterol saturation o f bile. Nine patients undergoing surgery for stones in the common bile duct were fitted with T-tubes in the common bile duct peroperatively; the side arm of the T-tube was left open postoperatively, creating a biliary fistula. All patients were given 6 days' treatment with pravas tatin (20 mg b.i.d.) following the operation. Bile was collected from the T-tube, in 12-h fractions during this period and for another 3 day s after termination of the treatment. Plasma levels of lipoproteins an d lathosterol - reflecting cholesterol synthesis - were determined on several occasions. After cessation of pravastatin treatment, the plasm a levels of total cholesterol and LDL-cholesterol increased by 21% and 33% respectively. High-density lipoprotein (HDL)-cholesterol did not change. The plasma level of lathosterol was increased two- to fourfold . Outputs of bile acids and phospholipids were significantly increased (23% and 10% respectively) after termination of treatment, whereas th e output of cholesterol was not significantly changed. Cholesterol sat uration was reduced by 20%, from 175 +/- 37% to 140 +/- 19%, but this change was not significant. The results indicate that, with the presen t experimental model (biliary diversion), the synthesis and biliary se cretion of bile acids seem to be largely dependent on the de novo synt hesis of cholesterol in the liver, whereas the biliary output of chole sterol is not.