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

Article Details

Citation

Wang E, Casciano CN, Clement RP, Johnson WW

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

Pharm Res. 2001 Jun;18(6):800-6.

PubMed ID
11474784 [ View in PubMed
]
Abstract

PURPOSE: HMG-CoA reductase inhibitors (statins) are commonly prescribed for lipid lowering to treat hypercholesterolemia. Although they are well tolerated, 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 inhibitors, and statin oxidative metabolism is mediated by CYP3A4 as well as other CYP enzymes. However, these same drugs that exert a clinical pharmacokinetic effect on statin disposition are generally also P-gp substrates/inhibitors; hence, this transporter may be, or may contribute to, the mechanism of interaction. METHODS: This study shows directly, as well as quantifies, the inhibition of P-gp-mediated transport of a fluorescent marker substrate. RESULTS: Lovastatin and simvastatin are very potent and effective inhibitors of P-gp transport with IC50's of 26 and 9 microM, respectively, for the human enzyme. Atorvastatin is also an effective P-gp inhibitor, but at higher concentrations. 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 these statins on ATP consumption by P-gp was also assessed, and the Km results were congruent with the IC50 observations. CONCLUSIONS: Therefore, the clinical interactions of statins with other drugs may be due, in part or all, to inhibition of P-gp transport.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AtorvastatinP-glycoprotein 1ProteinHumans
No
Substrate
Inhibitor
Details
LovastatinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
SimvastatinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AtorvastatinP-glycoprotein 1IC 50 (nM)307000N/AN/ADetails
AtorvastatinP-glycoprotein 1IC 50 (nM)271000N/AN/ADetails
LovastatinP-glycoprotein 1IC 50 (nM)26000N/AN/ADetails
LovastatinP-glycoprotein 1IC 50 (nM)67000N/AN/ADetails
SimvastatinP-glycoprotein 1IC 50 (nM)46000N/AN/ADetails
SimvastatinP-glycoprotein 1IC 50 (nM)9000N/AN/ADetails