Comparative Hepatic and Intestinal Metabolism and Pharmacodynamics of Statins

• Published in: Drug metabolism and disposition 2021-08, Vol.49 (8), p.658-667
• Main Authors: Filppula, Anne M., Hirvensalo, Päivi, Parviainen, Heli, Ivaska, Vilma E., Lönnberg, K. Ivar, Deng, Feng, Viinamäki, Jenni, Kurkela, Mika, Neuvonen, Mikko, Niemi, Mikko
• Format: Article
• Language: English
• Subjects: Biotransformation; Cytochrome P-450 Enzyme System - metabolism; Cytosol - metabolism; Drug Design - methods; Drug Development - methods; Hepatobiliary Elimination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - classification; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Inhibitory Concentration 50; Intestines - metabolism; Liver - metabolism; Metabolic Clearance Rate - drug effects; Microsomes - physiology; Network Pharmacology
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.121.000406

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), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 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 3700 and 7400 µl/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20–840 µl/min per milligram). The acids had CLint values in the range