Effect of inhibiting HMG-CoA reductase on 7 alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis: contrasting findings in patients with and without prior up-regulation of the latter pathway

Background Atorvastatin is a potent inhibitor of 3-hydroxy-3-methyl-glutary l coenzyme A reductase, but its effect on bile acid synthesis is unknown. T he objectives of the study were to determine the effect of atorvastatin on bile acid synthesis in patients in whom this process had not been or had be en previously up-regulated by pharmacological or surgical means. Materials and methods Four patients with heterozygous familial hypercholest erolaemia (FH) and partial ileal bypass (PIB) and 19 FH heterozygotes witho ut PIB were treated with placebo, atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The non-PIB group was subsequently treate d with bile acid (BA) sequestrant 8-16 g daily followed by co-administratio n of atorvastatin 10 mg, each for 4 weeks. Plasma 7 alpha-hydroxy-4-cholest en-3-one (7 alpha-HCO), a well-validated marker of BA synthesis was measure d using high-performance liquid chromatography with UV detection. Results The plasma 7 alpha-HCO concentration was tenfold higher with placeb o in the PIB than in the non-PIB group (418.5 ng mL(-1) vs. 39.6 ng mL(-1) P = 0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40 mg daily (350.1 ng mL(-1) and 174.0 ng mL(-1), P = 0.007 respecti vely) but did not change significantly in the non-PIB group (44.7 ng mL(-1) and 28.3 ng mL(-) respectively). Administration of BA sequestrant to non-P IB patients increased 7 alpha-HCO to 197.4 ng mL(-1); this decreased to 106 .0 ng mL(-1) during co-administration of atorvastatin 10 mg daily (P = 0.00 01). Conclusion Atorvastatin decreases the rate of BA synthesis only if the latt er is up-regulated by PIB or BA sequestrants, presumably by limiting the su pply of newly synthesized free cholesterol.