Does pomegranate juice interact with simvastatin?/nThis is a general question.

Fråga: Does pomegranate juice interact with simvastatin? This is a general question.

Sammanfattning: Pomegranate juice have been shown to inhibit simvastatin metabolising enzymes, but only in vitro. There is no evidence of an interaction between pomegranate juice and simvastatin (or any other drugs) in vivo.

Svar: It has been well documented that grapefruit juice (but not common orange juice) inhibits drug metabolism via CYP3A enzymes, and that this interaction may have clinical consequences. Simvastatin is mainly metabolised by CYP3A4. The exposure of simvastatin, taken with one glass of grapefruit juice, will increase by severalfold, compared with when taken with water, and cases of myopathy, rhabdomyolysis and acute renal failure have been reported (1).

These findings have prompted researchers to investigate a variety of other fruit extracts for their ability to interfere with drug metabolising enzymes, even in the absence of case reports indicating any clinical problem.

A literature search revealed an abstract titled The effects of pomegranate juice on pharmacokinetics of simvastatin in (12) healthy Korean subjects. In this study, no interaction effect was seen, despite a high intake of 900 mL of pomegranate juice daily for three days before intake of simvastatin 40 mg, whereas the same amount of grapefruit juice clearly increased simvastatin exposure (2).

We have identified five other studies of the effect of pomegranate juice on drug metabolism (3-7). Three of the studies, all performed by the same research group on human liver microsomes in vitro, report an inhibitory effect of pomegranate juice on the metabolism of midazolam and carbamazepine via CYP3A (3,4) and on diclofenac metabolism via CYP2C9 (5). The inhibition of CYP3A was similar to that of grapefruit juice, while no positive control was used in the CYP2C9 study. Another research group, also studying the metabolism of midazolam in human liver microsomes, showed only very slight inhibition of pomegranate juice compared with grapefruit juice (6). One study only was performed both in vitro and in human volunteers. Again, pomegranate juice did show an inhibitory effect on triazolam metabolism (via CYP3A) in preparations of human liver microsomes, to almost the same extent as did grapefruit juice. However, in 13 healthy, male subjects, virtually no effect was seen on midazolam exposure, either after oral or intravenous administration, after intake of 227 mL of commercially produced pomegranate juice (7).

We also found a single case report concerning a possible interaction between pomegranate juice and rosuvastatin. A 48-year-old man took rosuvastatin 5 mg every other day for 17 months. Three weeks after having started drinking pomegranate juice 200 mL twice weekly, he presented with muscle pain and an elevated serum creatine kinase level. However, he hade previously had elevated creatine kinase levels both with (simvastatin, atorvastatin) and without statin treatment and had a family history of malignant hyperthermia (8).