Vol. 291, Issue 1, 131-139, October 1999

Small Intestinal Metabolism of the 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitor Lovastatin and Comparison with Pravastatin¹

Wolfgang Jacobsen, Gabriele Kirchner, Katrin Hallensleben, Laviero Mancinelli, Michael Deters, Ingelore Hackbarth, Karen Baner, Leslie Z. Benet, Karl-Friedrich Sewing and Uwe Christians

Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California (W.J., L.M., K.B., L.Z.B., U.C.); Institut für Allgemeine Pharmakologie, Medizinische Hochschule Hannover, Hannover, Germany (G.K., K.H., I.H., K.-F.S.); Institut für Pharmakologie und Toxokologie, Universität Rostock, Rostock, Germany (M.D.); and Department of Cardiothoracic Surgery, Stanford University Medical School, Stanford, California (U.C.)

We compared the intestinal metabolism of the structurally related 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin and pravastatin in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6'-hydroxy (apparent K_m = 11.2 ± 3.3 µM) and 6'-exomethylene (apparent K_m = 22.7 ± 9.0 µM) lovastatin. The apparent K_m values were similar for lovastatin metabolism by human liver microsomes. 6'-Hydroxylovastatin formation by pig small intestinal microsomes was inhibited with the following inhibition K_i values: cyclosporine, 3.3 ± 1.2 µM; ketoconazole, 0.4 ± 0.1 µM; and troleandomycin, 0.8 ± 0.9 µM. K_i values for 6'-exomethylene lovastatin were similar. Incubation of pravastatin with human small intestinal microsomes resulted in the generation of 3',5',6'-trihydroxypravastatin (apparent K_m = 4560 ± 1410 µM) and hydroxypravastatin (apparent K_m = 5290 ± 1740 µM). In addition, as in the liver, pravastatin was metabolized in the small intestine by sulfation and subsequent degradation to its main metabolite 3'-iso-pravastatin. It was concluded that lovastatin is metabolized by cytochrome P-450 3A enzymes in the small intestine. Compared with lovastatin, the cytochrome P-450-dependent intestinal intrinsic clearance of pravastatin was >5000-fold lower and cannot be expected to significantly affect its oral bioavailability or to be a significant site of drug interactions.