Bailey and colleagues1 are to be commended for highlighting the potential of many medications to interact with grapefruit.1 However, one medication on their list (Table 11) deserves closer scrutiny.
At first glance, clopidogrel seems to fit the criteria of a medication that is a known substrate of CYP3A4 with low total bioavailability, but on closer examination the issue is less clear.
First, clopidogrel is a prodrug that needs to be metabolized to its active form.2 Therefore, it is the only medication listed in Table 11 whose interaction with grapefruit via CYP3A4 may lead to a loss of efficacy instead of toxicity (this was correctly stated in Table 11). However, the biotransformation of clopidogrel to its active form is a two-step process involving multiple CYP isoenzymes. Only in the second step in the process is CYP3A4 involved.3 Whether intestinal CYP3A4 (as opposed to hepatic CYP3A4) is even involved in this second step is unclear.
Second, the enzyme that is primarily responsible for the low bioavailability of clopidogrel is not a cytochrome P450 enzyme at all. Instead, 85% of clopidogrel is metabolized to an inactive compound through esterase enzymes.2 Interestingly, some suggest that grapefruit juice may inhibit intestinal esterase enzymes.4 If this were the case, grapefruit may increase the amount of parent drug available to be converted to its active form, which could lead to increased antiplatelet effect. Therefore, given the complex metabolic pathway of clopidogrel, what, if any, effect grapefruit would have on pharmacokinetics or pharmacodynamics of this agent is not clear. A randomized study examining the effect of grapefruit juice on the antiplatelet activity of clopidogrel will hopefully shed more light on this issue (ClinicalTrials.gov: NCT00817999).