PURPOSE: Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. METHODS: A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24 h after single oral doses of 40-mg lovastatin. RESULTS: Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. CONCLUSION: This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.
PURPOSE: Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. METHODS: A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24 h after single oral doses of 40-mg lovastatin. RESULTS: Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. CONCLUSION: This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.
Authors: K P Vyas; P H Kari; S M Pitzenberger; R A Halpin; H G Ramjit; B Arison; J S Murphy; W F Hoffman; M S Schwartz; E H Ulm Journal: Drug Metab Dispos Date: 1990 Mar-Apr Impact factor: 3.922