In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin.

We demonstrated that naringenin (NRG), the aglycon form of naringin present in grapefruit juice inhibits in vitro the metabolism of simvastatin (SV), a HMG-CoA reductase inhibitor. SV undergoes an important first pass metabolism and this is thought to be partly responsible for its low bioavailability after oral administration. SV is a prodrug that requires metabolic activation through hydrolysis by esterases. In addition, SV is a substrate for cytochrome P450 enzymes. NRG, a potent inhibitor of cytochrome P450 enzymes, interferes with the isoenzymes of cytochrome P450 involved in the hepatic metabolism of SV. NRG inhibits the metabolism of SV in rat hepatocytes (the intrinsic clearance of SV decreases from 26.2 microl/min/10(6) cells in absence of NRG to 4.15 microl/min/10(6) cells in presence of 50 microM NRG). This inhibition is more pronounced in hepatocytes (Ki value approximately 5 microM) than in liver microsomes (Ki approximately 23 microM and approximately 30 microM in human and rat liver microsomes respectively). Therefore, the hepatocytes seem to be the best approach for in vitro interaction study between SV and NRG ; and this should be taken into account in the in vitro/in vivo extrapolation. If this interaction were confirmed in man, the doses of SV should be reduced when co-administered with grapefruit juice because of increased bioavailability of SV.