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European Journal of Clinical Pharmacology

, Volume 58, Issue 10, pp 663–668 | Cite as

Identification of epoxybergamottin as a CYP3A4 inhibitor in grapefruit peel

  • H. Wangensteen
  • E. Molden
  • H. Christensen
  • K. E. Malterud
Pharmacokinetics and Disposition

Abstract

Objective

The oral availability of many drugs metabolised by the enzyme cytochrome P 450 3A4 (CYP3A4) is increased if co-administered with grapefruit juice. Extracts from grapefruit peel have also demonstrated inhibitory activity and, during commercial manufacturing of grapefruit juice, inhibitory components might be squeezed into the juice from the peel. Thus, the aim of this in vitro study was to identify CYP3A4 inhibitors in grapefruit peel.

Methods

Grapefruit peel was extracted with diethyl ether, and the extract was further fractionated by normal-phase chromatography. Fractions demonstrating significant CYP3A4 inhibitory activity, as measured by the relative reduction in N-demethylation of diltiazem in transfected human liver epithelial cells, were subsequently separated by preparative thin-layer chromatography. Constituents of the fractions and isolated compounds were identified by nuclear magnetic resonance spectroscopy. Analysis of diltiazem and N-demethyl-diltiazem was performed using high-performance liquid chromatography.

Results

Of the identified components in grapefruit peel, only epoxybergamottin demonstrated a concentration-dependent inhibition of the CYP3A4-mediated N-demethylation of diltiazem. The IC50 value was calculated to be 4.2±1.1 µM. Coumarins without the furan ring and flavonoids isolated from grapefruit peel did not interfere with the metabolism of diltiazem. The results indicated the presence of other CYP3A4 inhibitors in grapefruit peel, but these agents were lost during the purification process excluding their identification.

Conclusion

The furanocoumarin epoxybergamottin, present in grapefruit peel, is an inhibitor of CYP3A4. In commercial manufacturing of grapefruit juice, epoxybergamottin is possibly distributed into the juice. During manufacturing, however, epoxybergamottin may be hydrolysed to 6´,7´-dihydroxybergamottin, which has been suggested as an important CYP3A4 inhibitor in grapefruit juice.

Keywords

Grapefruit peel Furanocoumarins Epoxybergamottin 

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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • H. Wangensteen
    • 1
  • E. Molden
    • 2
  • H. Christensen
    • 2
  • K. E. Malterud
    • 1
  1. 1.Department of PharmacognosySchool of Pharmacy, University of OsloOsloNorway
  2. 2.Department of PharmacologySchool of Pharmacy, University of OsloNorway

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