Posted 04 January 2007 - 03:31 AM
I'm taking pomegranate extract daily, so I looked further into the p450 inhibition issue. It turns out that many fruit juices are p450 inhibitors, chiefly CYP3A. (CYP = CYtochrome P450) Pomegranate juice is also a 2C9 inhibitor (PMID: 17132763). The juices are 3A inhibitors in the following order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry. (PMID: 16415112) Starfruit is also inhibitory, although I don't know where it fits in this scheme. Lime juice was seen to be an apparent 3A4 inhibitor in some subjects. (PMID: 12811362) Even red wine is a mild 3A4 inhibitor, and can lead to clinically relevant inhibition in some people. (PMID: 11452240)
The fruit juices all appear to act via a mechanism-based process. This means that they are covalently alterning the p450 enzyme rather than just taking up space in the active site while they are present in high concentration. As such, the inhibition continues until the enzyme is recycled. After grapefruit juice consumption, it may take from 3 (PMID: 12891222) to 7 (PMID: 11061578) days for the metabolism of certain drugs to return to normal.
Several studies looked at fresh versus processed or heat treated juices, and saw no differences. This suggests that the inhibition is due to a reasonably robust small molecule, rather than a proteolytic activity.
The juices appear to affect only the enteric p450s. The hepatic p450s seem to be left alone, from my reading. Apparently some people have more p450 activity in the gut (and less in the liver?) than others, so the juices hit them harder.
Are these inhibitions clinically relevant? Yes, it appears that they are. "When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-infinity)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control." (PMID: 11061578) "48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4." (PMID: 16923466) This paper was published shortly before the paper that showed that pomegranate juice was a 2C9 inhibitor, and sure enough, rosuvastatin is metabolized by 2C9.
Pomegranate juice harmful? Like everything else that we are running experiments on ourselves with, it should be treated as a drug. In combination with statins, high dose pomegranate is indeed dangerous. Grapefruit juice is worse. If you are using these juices, you should make sure that any other drugs you take are safe in the presence of a 3A4 or 2C9 inhibitor.
From my own experience, pomegranate (at least in the dose of extract I use, approximately 660 cc/day juice equivalent) is not a super strong 3A4 inhibitor. One of my chronic medications is a 3A4 substrate, and I have used it with clarithromycin, an antibiotic (biaxin) that is a powerful 3A4 inhibitor. With biaxin, I strongly feel the overdose of the other med in a few days. I've been using pomegranate for about 2 weeks, and just the other night noticed a slight tinge of OD. So it's there, but not very strong. But that's me, and that's a medicine with a pretty good therapeutic index. I will keep taking pomegranate because it does great things, but will titrate my other meds as needed.
By the way, (as if this post were not long enough...) my doctor, a pretty smart guy, happily prescribed a 3A4 substrate and a potent 3A4 inhibitor to me at the same time, and my pharmacist cheerfully dispensed them. In theory, that never should have happened- so much for the theory. Whenever you get a prescription medication, ask the pharmacist for a package insert. (the one for the pros, not the Readers Digest version that they print out for consumers) It will usually discuss the metabolism of the drug in detail, and you can figure out for yourself if you might have a problem or not.
Thanks for the heads up on this, greece.
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