Marginal increase of sunitinib exposure by grapefruit juice

Cancer Chemother Pharmacol. 2011 Mar;67(3):695-703. doi: 10.1007/s00280-010-1367-0. Epub 2010 May 29.


Purpose: The drug label of sunitinib includes a warning for concomitant use of grapefruit juice (GJ) but clinical evidence for this drug interaction is lacking. The aim of this study is to determine the effect of GJ, a potent intestinal cytochrome P450 (CYP) 3A4 inhibitor, on steady-state sunitinib pharmacokinetics (PK).

Methods: Sunitinib PK was evaluated in eight cancer patients receiving sunitinib monotherapy in a "4 weeks on-2 weeks off" dose regimen. Serial blood samples for PK analysis of sunitinib were collected on two separate days. On both PK days, patients received a single oral dose of 7.5-mg midazolam as a phenotypic probe for assessment of intestinal CYP3A4 activity. The first PK day was at steady-state sunitinib PK (between days 14-20), the second PK day was on day 28. On days 25, 26 and 27, 200-mL GJ was consumed 3 times a day. The effect of GJ on sunitinib exposure was assessed by comparing sunitinib PK with and without GJ.

Results: Concomitant use of GJ and sunitinib resulted in an 11% increase of the relative bioavailability of sunitinib (P < 0.05). The effect of GJ on CYP3A4 activity was confirmed by an increase of ~50% of mean midazolam exposure (AUC(0-24 h)) from 122.1 to 182.0 ng h/mL (P = 0.034).

Conclusion: GJ consumption results in a marginal increase in sunitinib exposure which is not considered clinically relevant. There is no clinical evidence underscoring the warning in the sunitinib drug label regarding concomitant use of GJ.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Area Under Curve
  • Beverages / adverse effects
  • Biological Availability
  • Citrus paradisi / adverse effects*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Labeling
  • Female
  • Food-Drug Interactions*
  • Humans
  • Indoles / administration & dosage
  • Indoles / pharmacokinetics*
  • Male
  • Midazolam / metabolism
  • Middle Aged
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacokinetics*
  • Sunitinib


  • Antineoplastic Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Indoles
  • Pyrroles
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam
  • Sunitinib