Filppula, AM; Hirvensalo, P; Parviainen, H; Ivaska, VE; Lönnberg, KI; Deng, F; Viinamäki, J; Kurkela, M; Neuvonen, M; Niemi, M
This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and their metabolites were investigated using human liver microsomes (HLMs), intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 (CYP) enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism (intrinsic clearance (CLint) values of 3,700 and 7,400 µl/min/mg), while the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20-840 µl/min/mg). The acids had CLint values in the range <0.1-80 µl/min/mg. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CLint values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modelling. Significance Statement The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, our findings are applicable for use in comparative systems pharmacology modelling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.