Abstract
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 (AUC0-∞) 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.
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Acknowledgements
This study was supported in part by grant ITS/174/00 from the Innovation and Technology Commission of the Government of Hong Kong SAR. We would like to thank Ms. Evelyn Chau and Ms. Sherry Lam for their valuable technical assistance in this investigation.
Conflicts of interest/disclosure
Prof. Tomlinson has received research funding from AstraZeneca, Merck Sharp & Dohme, Novartis and Pfizer and has served as advisor or consultant for Merck Sharp & Dohme and Pfizer. He has received grants for educational activities from and is a speaker for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Pfizer. None of the other authors has any conflicts of interest directly relevant to the content of this study.
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Yin, O.Q.P., Mak, V.W.L., Hu, M. et al. Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects. Eur J Clin Pharmacol 68, 943–949 (2012). https://doi.org/10.1007/s00228-011-1202-5
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DOI: https://doi.org/10.1007/s00228-011-1202-5