Mechanism of drug-drug interactions between warfarin and statins

The anticoagulant drug warfarin and the lipid lowering statin drugs are commonly co-administered to patients with cardiovascular disease. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in CYP-mediated drug metabolism or disturbances of drug-protein binding to serum albumin. However, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. It was the purpose of this research project to further explore the etiology of the DDIs between warfarin and several statin drugs in order to inform safer prescribing practices. An analytical method was successfully developed and validated to study the mechanism of DDIs. Role of different ADME properties was evaluated to understand the mechanism of these DDIs. The results showed that different statins show different mechanisms, CYP mediated inhibition of warfarin metabolism by statins being the major cause for these DDIs contributing to the DDIs of all the statins. PPB displacement may play a role in DDIs between warfarin and fluvastatin, but it does not play any role in DDIs involving warfarin with other statins. Tested drug transporters did not play any role in these DDIs.