Role of P-glycoprotein in Statin Drug Interactions

• Published in: Pharmacotherapy Vol. 26; no. 11; pp. 1601 - 1607
• Main Authors: Holtzman, Carol W., Wiggins, Barbara S., Spinler, Sarah A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2006; Pharmacotherapy
• Subjects: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Area Under Curve; atorvastatin; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Drug Interactions; fluvastatin; General and cellular metabolism. Vitamins; HMG-CoA reductase inhibitor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; lovastatin; Medical sciences; multidrug-resistant transporter protein 1; P-glycoprotein; P-gp; Pharmacology. Drug treatments; pravastatin; rosuvastatin; simvastatin; statin; Biological transport; P Glycoprotein; Lovastatin; Rosuvastatin; Pravastatin; Fluvastatin; Multiple resistance; HMG-CoA reductase inhibitor; Drug interaction; Carrier protein; Transmembrane protein; P-gp; Enzyme; Simvastatin; Enzyme inhibitor; Statin derivative; Coenzyme; multidrug- resistant transporter protein 1; P-glycoprotein; statin; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Atorvastatin; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Antilipemic agent; Reductase
• ISSN: 0277-0008; 1875-9114
• DOI: 10.1592/phco.26.11.1601

Understanding the mechanisms of drug interactions with 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) has become increasingly important because of the potential for serious adverse effects, most notably myopathy. Most of the evidence supports the role of cytochrome P450 (CYP) isoenzymes in many of these drug interactions. However, P‐glycoprotein (P‐gp), an efflux protein located in the gastrointestinal tract, placenta, kidneys, brain, and liver, may also play a role. Results of several studies with in vitro models have shown that lovastatin, simvastatin, and atorvastatin are inhibitors for P‐gp and may be substrates for this transporter as well. Pravastatin and fluvastatin consistently demonstrate no significant inhibition of P‐gp. Drug interaction studies involving statins and digoxin support a role for P‐gp. Many additional drugs such as diltiazem, verapamil, itraconazole, ketoconazole, and cyclosporine, as well as dietary supplements such as St. John's wort and grapefruit juice, interact with statins and are modulators of both CYP3A4 and P‐gp. However, the role of P‐gp in these specific drug interactions remains unclear.