Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver

In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A reductase inhi bitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6'beta-hydroxy [Michae lis-Menten constant (K-m): 7.8 +/- 2.7 mu M] and 6'-exomethylene lovastatin (K-m,10.3 +/- 2.6 mu M). 6'beta-Hydroxylovastatin formation in the liver w as inhibited by the specific CYP3A inhibitors cyclosporine (K-i, 7.6 +/- 2. 3 mu M), ketoconazole (K-i, 0.25 +/- 0.2 mu M), and troleandomycin (K-i, 26 .6 +/- 18.5 mu M) Incubation of pravastatin with human liver microsomes res ulted in the generation of 3'alpha,5' beta,6' beta-trihydroxy pravastatin ( K-m, 4,887 +/- 2,185 mu M) and hydroxy pravastatin (K-m, 20,987 +/- 9,389 m u M). The formation rates of 3'alpha,5' beta,6' P-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 mu M pravastatin) 1.9 +/- 0.6 pmol .min(-1).pmol CYP3A4 and 0.06 +/- 0.04 pmol.min(-1).pmol CYP3A5, and the fo rmation rates of hydroxy pravastatin were 0.12 +/- 0.02 pmol.min(-1).pmol C YP3A4 and 0.02 +/- 0.004 pmol.min(-1).pmol CYP3A5. The specific CYP3A inhib itors cyclosporine, ketoconazole, and troleandomycin significantly inhibite d hydroxy pravastatin formation by human liver microsomes, but only ketocon azole inhibited 3'alpha,5'beta,6'beta-trihydroxy pravastatin formation, sug gesting that other CYP enzymes are involved in its formation. It is conclud ed that, compared with lovastatin [CLint formation 6'beta-hydroxylovastatin (mu l.min(-1).mg(-1)): 199 +/- 248, 6'-exomethylene lovastatin: 138 +/- 10 4)], CYP3A-dependent metabolism of pravastatin [CLint formation 3'alpha,5'b eta,6'beta-trihydroxy pravastatin (mu l.min(-1).mg(-1)): 0.03 +/- 0.03 and hydroxy pravastatin: 0.02 +/- 0.02] is a minor elimination pathway. In cont rast to lovastatin, drug interactions with pravastatin CYP3A-catalyzed meta bolism cannot be expected to have a clinically significant effect on its ph armacokinetics.