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

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′β-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′β-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′α,5′β,6′β-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′α-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.