BILE-ACID METABOLISM AND BILIARY-SECRETION IN PATIENTS RECEIVING ORTHOTOPIC LIVER-TRANSPLANTS - DIFFERING EFFECTS OF CYCLOSPORINE AND FK-506

Bile acid metabolism and biliary secretion were characterized in the f irst 2 wk after orthotopic liver transplantation in 15 patients receiv ing cyclosporine and in five patients receiving FK 506. Analyses were performed on hepatic bile obtained by T-tube drainage; values obtained were compared with literature values for bile samples obtained in pat ients who had undergone cholecystectomy. Biliary bile acid output, whi ch is equivalent to bile acid biosynthesis from cholesterol, was low ( mean +/- S.E.M.) and increased with time: day 1, 0.50 +/- 0.1 mmol/day ; day 3, 0.8 +/- 0.1 mmol/day; and day 6, 1.6 +/- 0.5 mmol/day. Chenod eoxycholic acid biosynthesis, as percent of total bile acid biosynthes is, was abnormally low in patients receiving cyclosporine (16.2 +/- 1. 1) but not in patients receiving FK 506 (38.2 +/- 4.8) (p < 0.005). Be fore the T-tube was clamped, the proportion of deoxycholic acid (a sec ondary bile acid formed by bacterial 7-dehydroxylation of cholic acid) was low in both groups: cyclosporine, 0.4 +/- 0.1; FK 506, 4.8 +/- 2. 5 (p < 0.01). The mean concentration of bile acids in hepatic bile bet ween days 4 and 11 did not differ significantly between groups: cyclos porine, 7.7 +/- 1.3 mmol/L; FK 506 4.3 +/- 0.7 mmol/L (mean +/- S.E.M. ). (These values are similar to those reported for patients who have u ndergone cholecystectomy.) Bile acid-dependent bile how, expressed as apparent choleretic activity (microliters of bile per micromole of bil e acid output), was markedly elevated: in patients receiving cyclospor ine the value was 129, and in patients receiving FK 506 the value was 220. (In patients who have undergone cholecystectomy, this value is le ss than 30.) It is concluded that canalicular secretion of bile acids is markedly decreased in the immediate postoperative period after live r transplantation, whereas bile how is relatively unimpaired, possibly because of impaired biliary duct function. During this period, admini stration of cyclosporine but not FK 506 causes a selective reduction i n chenodeoxycholic acid biosynthesis, probably attributable to its kno wn inhibition of cholesterol 27-hydroxylase.