Is there a pharmacokinetic drug interaction between ezetimibe (Ezetrol) and grapefruit juice?

Fråga: Is there a pharmacokinetic drug interaction between ezetimibe (Ezetrol) and grapefruit juice?

Sammanfattning: There is no evidence for a clinically significant pharmacokinetic drug interaction between ezetimibe and grapefruit juice in the literature. The risk of a pharmacokinetic drug interaction appears to be relatively small due to ezetimibes lack of affinity for CYP isoenzymes.

Svar: Grapefruit juice inhibits CYP3A4 in the intestinal wall increasing the bioavailability of orally administered drugs that are metabolized by this enzyme (1, 2). Grapefruit juice has little effect on hepatic CYP3A4 except at very high dosages. The time course of recovery from CYP3A inhibition after a single exposure to grapefruit juice is about three days (1). Drug interactions with grapefruit juice are especially important for drugs with a low therapeutic index and low oral bioavailability.

Ezetimibe is rapidly absorbed after oral administration and extensively metabolised (80%) by UGT mediated glucuronidation, primarily in the small intestine and the liver, to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide), which is localised in the small intestine and inhibits the absorption of cholesterol (3, 4). Ezetimibe-glucuronide is the major drug-derived compound detected in plasma. The exposure (AUC) of the parent substance ezetimibe represents only 10% of total ezetimibe, including metabolites. The drug is excreted in the faeces.

Ezetimibe undergoes minimal cytochrome P450-catalyzed oxidative metabolism. In vitro data shows that ezetimibe is an inhibitor of CYP3A4 and CYP2C8 (4). However, no clinically significant pharmacokinetic drug interactions were seen in vivo between ezetimibe and substrates of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP3A4 or N-acetyltransferase (3, 4). The authors of a review article argue that the risk of drug interactions with ezetimibe appears to be relatively small due to its extensive glucuronidation, and lack of affinity for CYP isoenzymes and P-glycoprotein-mediated transport (4).

Only a few cases of overdosage with ezetimibe have been reported and most have not been associated with adverse effects. Serious adverse effects have not been reported (3).

There is no warning for concomitant use of grapefruit juice and ezetimibe neither in the Summary of Product Information for Ezetrol (ezetimibe) (3), nor in the drug interaction databases Sfinx and Stockley´s Drug Interactions (5, 6). There are no reports of concomitant use of ezetimibe and grapefruit juice in the literature. One case report describes a 48-year-old man who had been treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months (7). He developed rhabdomyolysis three weeks after he had started drinking pomegranate juice (200 ml twice weekly), which like grapefruit juice is an inhibitor of intestinal CYP3A4. However, the authors suggest that the rhabdomyolysis was caused by a drug interaction between pomegranate juice and rosuvastatin. Ezetimibe was not the suspected drug. Greenblatt DJ, von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, et al. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther. 2003;74(2):121-129. Drugline 24280, year 2012 SPC Ezetrol MSD via www.fass.se, cited 161124 Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clinical pharmacokinetics. 2005;44(5):467-494. Sfinx via www.janusinfo.se, cited 161124 Stockley´s Drug interactions via Medicines Complete, cited 161124 Sorokin AV, Duncan B, Panetta R, Thompson PD. Rhabdomyolysis associated with pomegranate juice consumption. Am J Cardiol. 2006;98(5):705-706.