TY - JOUR T1 - 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 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 173 LP - 179 VL - 27 IS - 2 AU - Wolfgang Jacobsen AU - Gabriele Kirchner AU - Katrin Hallensleben AU - Laviero Mancinelli AU - Michael Deters AU - Ingelore Hackbarth AU - Leslie Z. Benet AU - Karl-Fr. Sewing AU - Uwe Christians Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/173.abstract N2 - 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 inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6′β-hydroxy [Michaelis-Menten constant (Km): 7.8 ± 2.7 μM] and 6′-exomethylene lovastatin (Km,10.3 ± 2.6 μM). 6′β-Hydroxylovastatin formation in the liver was inhibited by the specific CYP3A inhibitors cyclosporine (Ki, 7.6 ± 2.3 μM), ketoconazole (Ki, 0.25 ± 0.2 μM), and troleandomycin (Ki, 26.6 ± 18.5 μM). Incubation of pravastatin with human liver microsomes resulted in the generation of 3′α,5′β,6′β-trihydroxy pravastatin (Km, 4,887 ± 2,185 μM) and hydroxy pravastatin (Km, 20,987 ± 9,389 μM). The formation rates of 3′α,5′β,6′β-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 μM pravastatin) 1.9 ± 0.6 pmol·min−1·pmol CYP3A4 and 0.06 ± 0.04 pmol·min−1·pmol CYP3A5, and the formation rates of hydroxy pravastatin were 0.12 ± 0.02 pmol·min−1·pmol CYP3A4 and 0.02 ± 0.004 pmol·min−1·pmol CYP3A5. The specific CYP3A inhibitors cyclosporine, ketoconazole, and troleandomycin significantly inhibited hydroxy pravastatin formation by human liver microsomes, but only ketoconazole inhibited 3′α,5′β,6′β-trihydroxy pravastatin formation, suggesting that other CYP enzymes are involved in its formation. It is concluded that, compared with lovastatin [CLint formation 6′β-hydroxylovastatin (μl·min−1·mg−1): 199 ± 248, 6′-exomethylene lovastatin: 138 ± 104)], CYP3A-dependent metabolism of pravastatin [CLint formation 3′α,5′β,6′β-trihydroxy pravastatin (μl·min−1·mg−1): 0.03 ± 0.03 and hydroxy pravastatin: 0.02 ± 0.02] is a minor elimination pathway. In contrast to lovastatin, drug interactions with pravastatin CYP3A-catalyzed metabolism cannot be expected to have a clinically significant effect on its pharmacokinetics. The American Society for Pharmacology and Experimental Therapeutics ER -