Effect of grapefruit juice on the disposition of omeprazole

In a recent issue of this journal, Tassaneeyakul et al. reported the effect of grapefruit juice (GFJ) intake on the disposition of omeprazole and its primary metabolites following a single oral dose to 13 healthy volunteers, two of whom being poor metabolisers (PM) for cytochrome P450 (CYP) 2C19 [1]. As recalled by the authors, furocoumarins in GFJ have been implicated in several drug interactions involving CYP3A4 substrates, including felodipine, cyclosporin, midazolam, and saquinavir [2]. However, unlike stated in their introduction, other beverages have been shown to alter the disposition of some of these drugs. For example, juices prepared from the Seville (sour) orange, pummelo and sweetie fruit, and red wine contain many of the furocoumarins and flavonoids found in GFJ, including 6′, 7′ dihydroxybergamottin, that are known to inhibit various CYP and/or transporter activities in vivo and/or in vitro [3–7]. The authors reported that, as with water, GFJ had virtually no effect on the average area under the concentration-time curve (AUC), maximal plasma concentration (Cmax), time to reach Cmax (tmax), and elimination half-life (t½,z) of omeprazole and its CYP2C19-mediated metabolite, 5-hydroxyomeprazole (Table 1). In addition, while GFJ also had no effect on the tmax and t½,z of the CYP3A4-mediated metabolite, omeprazole sulphone, the average AUC and Cmax for this metabolite were significantly reduced. These findings would suggest that omeprazole metabolism is primarily mediated by CYP2C19 when CYP3A4 is inhibited. However, because 5-hydroxyomeprazole is further metabolized to a CYP3A4-mediated sulphone, one might also have expected an increase in 5-hydroxyomeprazole AUC following GFJ intake. The authors further reported no difference between extensive metabolisers (EM) and PM regarding GFJ effects on omeprazole pharmacokinetics. However, Figure 2b (lower right curve) provided incomplete data describing omeprazole sulphone disposition in the two CYP2C19 PM, making the calculation of the mean t½,z questionable. Moreover, despite the fact that the authors found a 5-fold higher omeprazole AUC in PM compared with EM, the data were pooled, which probably led to the wider-than-expected variability observed in both the AUC and Cmax of omeprazole. This method of analysis likely precluded the expected significant increase with GFJ. Nevertheless, if the authors are correct, and because omeprazole is generally well-tolerated and omeprazole AUC was not even increased by GFJ, then the clinical relevance of this interaction remains unclear [2]. In addition, given the 5-fold higher omeprazole AUC in PM compared with EM, one would expect CYP2C19 to be the major metabolic pathway for this drug even in absence of CYP3A4 inhibition. The decreased omeprazole sulphone Cmax and AUC without an accompanying change in omeprazole t½,z following GFJ intake was indeed most likely the result of inhibition of intestinal CYP3A4-mediated first-pass metabolism. However, CYP2C19 has been recently detected in human small intestinal microsomes, with protein content and catalytic activity comparable with those measured in liver microsomes [8]. In addition, the authors stated from their unpublished data that this isoform can be inhibited by various furocoumarins found in GFJ. Thus, inhibition of intestinal CYP2C19 by GFJ cannot be ruled out in the present study, despite its lack of effect on 5-hydroxyomeprazole AUC and Cmax. Again, pooling PM and EM data may have masked a difference in 5-hydroxyomeprazole AUC between water and GFJ intake. Likewise, inhibition of 5-hydroxyomeprazole secondary metabolism by the juice could have increased this metabolite's AUC but to a different extent between PM and EM, also masking a difference between the two treatment phases. The contribution of intestinal metabolism, as well as transport, in limiting the oral bioavailability of drugs is difficult to assess in humans in the absence of a specific and reliable probe(s) for each pathway. This is particularly true for drugs like omeprazole that undergo complex primary and secondary metabolism prior to reaching the portal circulation [1]. Addressing this critical issue in vivo is of particular interest and will likely require taking into account each of the relevant intestinal enzymes and/or transporters [9] potentially involved in the interaction, as well as the physicochemical conditions in the intestinal lumen, to improve our understanding of the effect of the intestinal barrier on oral drug absorption.