The Impact of Grapefruit Juice on the Response to Clopidogrel

Clopidogrel is a prodrug which is transformed in vivo to both an inactive metabolite through
esterases and an active form through a series of CYP-mediated steps.The CYP isoenzymes that
have been identified as being involved with the metabolism of clopidogrel include CYP1A2,
CYP2B6, CYP2C9, CYP2C19, and CYP3A4.There have been a number of reports published citing the
variability in response to clopidogrel with one of the potential influences on this
variability being drug interactions.Grapefruit juice (GFJ) has been extensively studied in
the area of interactions with medications due to its inhibition of both CYP3A4 and more
recently its inhibition of esterases. With clopidogrel being metabolized by both CYP3A4 and
esterases, there is a theoretical interaction between clopidogrel and GFJ. Whether this
potential interaction has an impact on clopidogrel's ability to affect platelet inhibition
is currently unknown.

This study will examine the effect of GFJ on the loading dose (300mg) of clopidogrel and
will evaluate the effect of GFJ on the maintenance dose (75mg/day) of clopidogrel. Subjects
will be randomized to either initially receive GFJ prior to their loading dose of
clopidogrel or receive GFJ prior to their second loading dose. The subjects who have been
randomized to receive GFJ initially will drink two small cans (11 oz total) of regular
strength GFJ in the morning, followed two hours later by a loading dose (300mg) of
clopidogrel and will then return to the clinic 6 hours after their loading dose to have
their platelet inhibition measured. Subjects will have ~ 5 milliliters (1 teaspoonful) of
whole blood drawn from an antecubital vein in their forearm via a 21 gauge needle attached
to a blue-top plastic vacuette sodium citrate blood collection (Greiner, Monroe, NC) tube to
test inhibition of platelet aggregation. After their first loading dose, a 2 week washout
period will follow to allow for their platelet aggregation to return to normal. Following
the washout period, the subjects will take their second loading dose of clopidogrel and
again return to the clinic for platelet inhibition measurement. The same timing will be
followed for the loading dose taken without prior GFJ.