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Vol. 31, Issue 1, 53-59, January 2003
Department of Anesthesiology, University of Michigan, Ann Arbor,
Michigan (T.C., L.W.); Veterans Affairs Medical Center, Ann Arbor,
Michigan (L.W.)
The prodrug clopidogrel (Plavix) is activated by cytochrome P450
(P450) to a metabolite that inhibits ADP-induced platelet aggregation. Clopidogrel is frequently administered to patients in
conjunction with the CYP3A4 substrate atorvastatin (Lipitor). Since
clinical studies indicate that atorvastatin inhibits the antiplatelet
activity of clopidogrel, we investigated whether CYP3A4 metabolized
clopidogrel in vitro. Microsomes prepared from dexamethasone-pretreated
rats metabolized clopidogrel at a rate of 3.8 nmol min
1
nmol of P4501, which is 65 and 1270% faster than the
rate of metabolism by microsomes from control and
-napthoflavone-treated rats, respectively. To identify the human
P450s responsible for clopidogrel oxidation, genetically engineered
microsomes containing a single human P450 isozyme were tested for their
ability to oxidize clopidogrel. CYP3A4 and 3A5 metabolized clopidogrel
at a significantly higher rate than eight other P450 isozymes,
suggesting that CYP3A4 and 3A5 are primarily responsible for in vivo
clopidogrel metabolism. Clopidogrel interacts with human CYP3A4 with a
spectral dissociation constant (Ks),
Km, and Vmax of
12 µM, 14 ± 1 µM and 6.7 ± 1 nmol min1
nmol P4501, respectively. Atorvastatin lactone, the
physiologically relevant substrate, inhibits clopidogrel with a
Ki of 6 µM. When clopidogrel and
atorvastatin are present at equimolar concentrations, clopidogrel metabolism is inhibited by greater than 90%. Since CYP3A4 and 3A5
metabolize clopidogrel faster than other human P450 isozymes and are
the most abundant P450s in human liver, they are predicted to be
predominantly responsible for the activation of clopidogrel in vivo.
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