An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins

ABSTRACT

Introduction

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lower cholesterol synthesis in patients with hypercholesterolemia. Increased statin exposure is an important risk factor for skeletal muscle toxicity. Potent inhibitors of cytochrome P450 (CYP) 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin, and atorvastatin. Fluvastatin is metabolized by CYP2C9, whereas pravastatin, rosuvastatin, and pitavastatin are unaffected by inhibition by either CYP. Statins also have different affinities for membrane transporters involved in processes such as intestinal absorption, hepatic absorption, biliary excretion, and renal excretion.

Areas covered

In this review, the pharmacokinetic aspects of drug–drug interactions with statins and genetic polymorphisms of CYPs and drug transporters involved in the pharmacokinetics of statins are discussed.

Expert opinion

Understanding the mechanisms underlying statin interactions can help minimize drug interactions and reduce the adverse side effects caused by statins. Since recent studies have shown the involvement of drug transporters such as OATP and BCRP as well as CYPs in statin pharmacokinetics, further clinical studies focusing on the drug transporters are necessary. The establishment of biomarkers based on novel mechanisms, such as the leakage of microRNAs into the peripheral blood associated with the muscle toxicity, is important for the early detection of statin side effects.

KEYWORDS:

• Atorvastatin
• rosuvastatin
• simvastatin
• CYP3A4
• SLCO1B1
• ABCG2
• genetic polymorphisms
• microRNA

Article highlights

• Myotoxicity is considered a statin exposure-dependent side effect, and clinical trials of statin interactions are important to understand their serious side effects.

• The pharmacokinetics of statins involve not only metabolic enzymes such as CYP3A4, but also drug transporters such as OATP1B1 and BCRP, and further clinical studies are important.

• The functional SNP, SLCO1B1 521T>C, had a strong effect on the AUC of atorvastatin and simvastatin acid, but the effect of rosuvastatin on the AUC was small.

• The higher frequency of ABCG2 421C>A variant alleles in East Asians may contribute to ethnic differences in pharmacokinetics of rosuvastatin.

• Circulating levels of muscle-specific miRNAs in peripheral blood are important for further study as a biomarker for predicting statin-induced skeletal muscle toxicity.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.