COMMENT:This pair of articles highlights the importance of not relying on invitro data in predicting drug interactions. In the Kim article, pomegranate juice showed invitro inhibition of CYP3A4 that was not supported in an invivo study by Farkas.

ABSTRACTS: Farkas D, Oleson LE, Zhao Y, Harmatz JS, Zinny MA, Court MH, Greenblatt DJ.Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice.J Clin Pharmacol. 2007 Mar;47(3):286-94.The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC (50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without preincubation of inhibitor with microsomes. After preincubation, the IC(50) for PJ increased to 0.97% (P < .05), whereas the IC(50) for GFJ decreased to 0.41% (P < .05), suggesting mechanism-based inhibition by GFJ but not PJ. Pretreatment of volunteer subjects (n = 13) with PJ (8 oz) did not alter the elimination half-life, volume of distribution, or clearance of intravenous midazolam (2 mg). Administration of PJ also did not affect C(max), total area under the curve (AUC), or clearance of oral midazolam (6 mg). However, GFJ (8 oz) increased midazolam C (max) and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values. Thus, PJ does not alter clearance of intravenous or oral midazolam, whereas GFJ impairs clearance and elevates plasma levels of oral midazolam.Kim H, Yoon YJ, Shon JH, Cha IJ, Shin JG, Liu KH Inhibitory effects of fruit juices on CYP3A activity. Drug Metab Dispos. 2006 Apr;34(4):521-3. Epub 2006 Jan 13

There have been very limited reports on the effects of commercial fruit juices on human CYP3A activity. Therefore, the inhibitory effects of readily available commercial fruit juices on midazolam 1′- hydroxylase activity, a marker of CYP3A, were evaluated in pooled human liver microsomes. The fruit juices investigated were black raspberry, black mulberry, plum, and wild grape. White grapefruit, pomegranate, and orange juice were used as positive and negative controls. The black mulberry juice showed the most potent inhibition of CYP3A except for grapefruit juice. The inhibition depended on the amount of a fruit juice added to the incubation mixture. The inhibitory potential of human CYP3A was in the order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry. The IC (50) values of all fruit juices tested were reduced after preincubation with microsomes in the presence of the NADPH-generating system, suggesting that a mechanism-based inhibitory component was present in these fruit juices, as in the case of grapefruit.

The results suggest that, like grapefruit juice, commercial fruit juices also have the potential to inhibit CYP3A-catalzyed midazolam 1′- hydroxylation. Therefore, in vivo studies investigating the interactions between fruit juices such as black mulberry and wild grape and CYP3A substrates are necessary to determine whether inhibition of CYP3A activity by fruit juices is clinically relevant.