Grapefruit juice (GFJ) has been found to interact with several medications, increasing their oral bioavailability and the risk of toxicity. Inhibition of CYP3A4 in the small intestine by flavonoids (such as naringin and naringenin) and furanocoumarins (including bergamottin and 6',7'-dihydroxybergamottin) present in GFJ seems to be the predominant mechanism, although P-glycoprotein and influx transporters in the small intestine are also involved. The quantity of interactive compounds ingested may affect the magnitude and mechanism of the food-drug interaction. Therefore, these four compounds were quantified by HPLC analysis in commercially available and fresh-squeezed GFJ and in grapefruit tissues. Considerable variability in naringin (174-1492 micromol/L), bergamottin (1.0-36.6 micromol/L), and 6',7'-dihydroxybergamottin (0.22-52.5 micromol/L) was observed, whereas naringenin could not be detected. White grapefruit showed higher concentrations of naringin and furanocoumarins located in the albedo and flavedo compared with red varieties. Findings from this study suggest considering concentrations of components with a potential for drug interactions in GFJ-drug interaction studies. The concentration of potentially contributing compounds may crucially influence the magnitude of observed interaction and impair direct comparison of studies in which different juices have been used.

Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG-CoA reductase inhibitors, calcium antagonists, and immunosuppressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P-glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.

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Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P max ‫؍‬ 13.6 ؋ 10 ؊6 cm ⅐ s ؊1 ; apparent K m ‫؍‬ 147 M), suggesting saturated transport at concentrations higher than 350 g/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This Pglycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.Fluoroquinolones (FQs) are one of the main classes of antimicrobial agents, with a broad spectrum of activity and a concentration-dependent killing effect (25,29). Moxifloxacin (MXF) is an FQ that has been shown to be effective against respiratory pathogens, including Haemophilus influenzae, Moraxella catarrhalis, and penicillin-resistant strains of Streptococcus pneumoniae (3,24). The use of MXF is recommended as therapy for patients with community-acquired pneumonia, exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, or tuberculosis (21). Pharmacokinetics of FQs have been studied in different tissues, such as the liver, kidney, and intestinal tract, and it appears that multiple transporters contribute to drug disposition (2). Active transport has been suggested for many FQs, involving mainly the ATP-binding cassette (ABC) transporter family (P-glycoprotein [P-gp] and multidrug resistance-related proteins [MRPs]). However, there is a lack of information regarding the mechanisms of MXF lung distribution. To our knowledge, cellular transport of MXF through the lung tissue is still unclear, and an understanding of its mechanisms would help to better predict its pulmonary disposition, which is directly linked to the bacterial killing effect. Moreover, when MXF is used as a second-line therapy or in combination with drugs such as rifampin (22), drug-drug interaction can occur, as presented in some rifampin-MXF interaction studies (23,30). In this particular case, MXF was recommended for the treatment of multidrugresistant tuberculosis and a decrease in MXF plasma concentration was observed in assoc...