NDLI: HMG-CoA Reductase Inhibitors (Statins) Characterized as Direct Inhibitors of P-Glycoprotein

Content Provider	Springer Nature Link
Author	Wang, Er jia Cascia, Christopher N. Clement, Robert P. Johnson, William W.
Copyright Year	2001
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 IC$_{50}$'s of 26 and 9 μM, 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 K$_{m}$ results were congruent with the IC$_{50}$ observations. Conclusions. Therefore, the clinical interactions of statins with other drugs may be due, in part or all, to inhibition of P-gp transport.
Starting Page	800
Ending Page	806
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	18
Issue Number	6
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2001-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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