Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters

ABSTRACT

Introduction: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3.

Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail.

Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.

KEYWORDS:

• CYP2C8
• drug-drug interaction
• gemfibrozil
• mechanism-based inhibition
• OAT3
• OATP1B1

Article highlights

• CYP2C8 is a drug metabolizing enzyme important for the elimination for many clinically used drugs.

• In vitro parent gemfibrozil is only a weak inhibitor of CYP2C8, but glucuronidation converts gemfibrozil to a mechanism-based inhibitor of CYP2C8, resulting in strong, long-lasting and fairly selective CYP2C8 inhibition in vivo.

• Gemfibrozil can cause clinically meaningful drug interactions with drugs that are CYP2C8 substrates.

• Gemfibrozil also has a short-lasting inhibitory effect on membrane transporters, such as OATP1B1 and OAT3, and the complex interaction mechanisms of gemfibrozil need to be taken into account when its effects on other drugs are estimated.

• Gemfibrozil can be used as a probe inhibitor of CYP2C8 in vivo.

• Also several other glucuronide metabolites of drugs have been identified as potential perpetrators in drug-drug interactions.

This box summarizes key points contained in the article.

Declaration of interest

JT Backman, PJ Neuvonen and M Niemi have filed a patent application concerning use of gemfibrozil. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was not funded.