HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein

Purpose. HMG-CoA reductase inhibitors (statins) are commonly prescribed for Lipid lowering to treat hypercholesterolemia. Although they are well toler ated, their pharmacokinetic interactions with other drugs can lead to some adverse clinical consequences. The avenue of interaction has been asserted to be CYP3A4 because most (or all) known interactions are with CYP3A4 inhib itors, and statin oxidative metabolism is mediated by CYP3A4 as well as oth er CYP enzymes. However, these same drugs that exert a clinical pharmacokin etic effect on statin disposition are generally also P-gp substrates/inhibi tors; hence, this transporter may be, or may contribute to, the mechanism o f interaction. Methods. This study shows directly, as well as quantifies, the inhibition o f P-gp-mediated transport of a fluorescent marker substrate. Results. Lovastatin and simvastatin are very potent and effective inhibitor s of P-gp transport with IC50's of 26 and 9 muM, respectively, for the huma n enzyme. Atorvastatin is also an effective P-gp inhibitor, but at higher c oncentrations. Uniquely, pravastatin, whose functional groups render it an inferior inhibitor of P-gp in the whole cell, had no effect in this assay. This result is consistent with known clinical interactions. The effect of t hese statins on ATP consumption by P-gp was also assessed, and the K-m resu lts were congruent with the IC50 observations. Conclusions. Therefore, the clinical interactions of statins with other dru gs may be due, in part or all, to inhibition of P-gp transport.