Inhibitors of CYP3A4

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Food and juices

A number of dietary components are known to inhibit the CYP3A4 system. The importance of this depends upon the individual, the inhibitor consumed and for how long, and of course the drug whose metabolism will be impaired. In the case of grapefruit juice the active inhibitors are known to be predominantly bergamottin and 6'7'-dihydroxybergamottin but other substances may be involved.[1]. Inhibition of intestinal CYP3A4 is initially most important, and this will cause significant interactions with some drugs predominantly metabolised on a first pass basis in the intestinal wall such as lovastatin. Constant consumption of grapefruit juice is more likely to produce hepatic CYP3A4 blockage. Of course the activity of grapefruit juice inactivation of CYP3A4 also depends upon the fruit the juice was prepared from, if it has been frozen, etc.[2] Red wine is a reversible inhibitor, at about 80% level by a different assay. Serville oranges, Pomelos' (a grapefruit from South India) and lime juice (at high concentration) have been shown to affect human drug metabolism of drugs such as tacrolimus.[3][4]

Fresh fruit juice inhibitors of this cytochrome system which metabolizes about 40 to 50% of the drugs on the market are in order of potency: [5][1]

  1. Star fruit (Averrhoa carambola) 99.9% blockage midazolam 1'-hydroxylation
  2. Pomegranate (Nephelium lappaceum) 96.8% blockage midazolam 1'-hydroxylation
  3. Pawpaw, common papaw, papaya (Carica papaya) 88.6% blockage midazolam 1'-hydroxylation
  4. Grapefruit (white) (Citrus paradise) 85.3% blockage midazolam 1'-hydroxylation

The following fresh fruit juices have much less activity (ie no more than 40% blockage) and are therefore effectively inactive

  • Valencia orange (Citrus sinensis)
  • Mango (Mangifera indica)
  • Rambutan (Passiflora edulis )
  • Kiwi fruit, Chinese gooseberry (Actinidia chinensis)
  • Dragon fruit (Hylocereus undatus)
  • Passion fruit (Punica granatum)
  • Tangerines - inactivity reported.

Herbal prepartions

Echinacea, particularly as a herbal extract of E. purpurea , ginkgo,soy based preparations and grape seed extract are herbal medicines which inhibit CYP3A4. General caution should be exerted with concurrent chemotherapy or other medications metabolized via the CYP 450 pathway for these products. Garlic is both an inhibitor and appears to be a potential CYP3A4 inducer. Even more important as an inducer is St John's wort.

Drugs

Inhibition causing in man raised drug levels and harm of other drugs (in brackets) metabolised by this enzyme have been reported with:

Potent Inhibitors

This article is a work in progress. Please feel free to contribute to it.



References

  1. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice. Clin Pharmacol Ther. 2003;73(6):529-37
  2. Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther. 2000 ;68(5) :468-77
  3. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice. Clin Pharmacol Ther. 2003;73(6):529-37
  4. Egashira K, Fukuda E, Onga T, Yogi Y, Matsuya F, Koyabu N, Ohtani H, Sawada Y. Pomelo-induced increase in the blood level of tacrolimus in a renal transplant patient. Transplantation. 2003 ;75(7):1057.
  5. Hidaka M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Okumura M, Kodama H, Arimori K. Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity. Drug Metab Dispos. 2004;32(6):581-3.
  6. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41(5):343-70
  7. Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther. 2005 Oct;78(4):388-99.
  8. Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol. 2006 Apr 27[Epub ahead of print]
  9. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41(5):343-70
  10. Nakamura K, Ariyoshi N, Iwatsubo T, Fukunaga Y, Higuchi S, Itoh K, Shimada N, Nagashima K, Yokoi T, Yamamoto K, Horiuchi R, Kamataki T. Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes. Biol Pharm Bull. 2005 May;28(5):882-5.
  11. Zhou Q, Zhou S, Chan E. Effect of omeprazole on the hydroxylation of warfarin enantiomers in human: in-vitro studies with liver microsomes and cDNA-expressed cytochrome P450 isozymes. Curr Drug Metab. 2005 Oct;6(5):399-411
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