Abbreviations: drug-drug interactions (DDI), human serum albumin (HSA), area under the curve fold ratio (AUCR), free energy change (ΔG), electron affinity (EA), reactive oxygen species (ROS), electrochemical peak reduction potentials (E p), linear multivariate correlation coefficient (R), standard error of the estimate (SEE), standard error (SE), anova F test statistic (F) Abstract A molecular orbital computational study of the statins and a comprehensive review of the literature have found that the lactone forms of statins play a major role in the transport of statins across the cell membrane, and in the metabolism and clearance from the body. The neutral lactone and acid statin species are preferentially transported across the cell membrane and consequentially preferentially metabolised and cleared. The preferred cellular uptake of statin lactones has implications for cytotoxicity in muscle tissue and other side effects. The uptake mechanism is a combination of passive facilitated diffusion and active permeation by OATP transporters. Quantitative models describing how uptakes rates, binding affinity between statins and OATP transporters, and the inhibition of statin-OATP transporters processes are related to the four principal determinants of cell membrane permeability (desolvation, lipophilicity, dipole moment and molecular volume) have been deduced. Cyclosporin and gemfibrozil competitive inhibition of statin-CYP metabolism correlates with desolvation, lipophilicity, dipole moment and electron affinity, which suggests that electron affinity, a measure of reduction potential, is a useful indicator of potential drug-drug interactions (DDI). A similar relationship was found with the statin inhibition of paclitaxel oxidation by CYP enzymes. An examination of drugs known to cause DDI with statins show that reduction potential and cellular uptake properties are useful predictors of DDI. These statistical models, supported by literature evidence, indicate the statin lactones play a previously unrecognized major role in statin therapeutics, and in side effects, cytotoxicity and DDI. It is likely that protonated statin lactones are the active species involved in electron transfer from the mitochondrial electron transfer processes that are a major cause of statin lactone induced myopathy. It has been demonstrated that the four parameter equation incorporating the independent variables desolvation, lipophilicity, dipole moment and molecular volume (or electron affinity) successfully correlates with passive and active transport processes, the statin inhibition of CYP metabolic enzymes, and the inhibition of HMGCoA reductase by statin anions. Objectives:  To understand the roles that statin acids and lactones play in statin therapeutics  To investigate the side effects of statin therapeutics by understanding the transport of statins across cell membranes  To investigate the metabolism and clearance of statins from the body  To investigate the cytotoxicity and drug-drug interactions of statins  To develop quantitative mechanistic models for statin inhibition, transport and metabolic processes