Small intestinal metabolism of the 3-hydroxy-3-methylglutary-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 pravastati n in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6' beta-hydroxy (apparent K-m = 11.2 +/- 3.3 mu M) and 6 '-exomethylene (apparent K-m = 22.7 +/- 9.0 mu M) lovastatin. The apparent K-m values were similar for lovastatin metabolism by human liver microsomes . 6' beta-Hydroxylovastatin formation by pig small intestinal microsomes wa s inhibited with the following inhibition K-i values: cyclosporine, 3.3 +/- 1.2 mu M; ketoconazole, 0.4 +/- 0.1 mu M; and troleandomycin, 0.8 +/- 0.9 mu M. K-i values for 6'-exomethylene lovastatin were similar. Incubation of pravastatin with human small intestinal microsomes resulted in the generat ion of 3'alpha,5'beta,6'beta-trihydroxypravastatin (apparent K-m = 4560 +/- 1410 mu M) and hydroxypravastatin (apparent K-m = 5290 +/- 1740 mu M). In addition, as in the liver, pravastatin was metabolized in the small intesti ne by sulfation and subsequent degradation to its main metabolite 3' alpha- iso-pravastatin. It was concluded that lovastatin is metabolized by cytochr ome P-450 3A enzymes in the small intestine. Compared with lovastatin, the cytochrome P-450-dependent intestinal intrinsic clearance of pravastatin wa s >5000-fold lower and cannot be expected to significantly affect its oral bioavailability or to be a significant site of drug interactions.