bergamottin and naringenin

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC

Topics: Animals; Cells, Cultured; Citrus paradisi; Computer Simulation; Dogs; Estrone; Flavanones; Flavones; Food-Drug Interactions; Fruit and Vegetable Juices; Furocoumarins; Hesperidin; Humans; Inhibitory Concentration 50; Models, Biological; Organic Anion Transporters

Grapefruit juice (GFJ) is known to affect the pharmacokinetics of a variety of drugs administered concomitantly and this is due to inhibition of intestinal CYP3A, a barrier protein for drug absorption. Some compounds such as furanocoumarin derivatives have been reported as inhibitors of the enzyme. On the other hand, inhibitory potentials of GFJ on CYP3A-oxidation activities differ widely between brands of juices. Information on the percentage contributed by ingredients in GFJ is also limited. Therefore, construction of prediction models for the CYP3A inhibitory potentials of GFJ brands was attempted by using concentrations of ingredients in GFJ. Concentrations of bergaptol, bergamottin, 6', 7'-dihydroxybergamottin, naringin, and naringenin in 23 kinds of GFJ were determined with high-performance liquid chromatography (HPLC). Furthermore, inhibitory effects on CYP3A activity were measured based on the initial rate for testosterone 6beta-hydroxylation in the presence of each GFJ. Results of multi-regression analyses between the ingredients and the enzymatic inhibitory effects revealed that concentrations of bergamottin, 6',7'-dihydroxybergamottin, and naringin were significant variables for CYP3A inhibition of GFJ. According to the standard partial regression coefficient for each explanatory variable, bergamottin and 6',7'-dihydroxybergamottin are the most important factors for inhibition. The multiple correlation coefficient (R) and the multiple correlation coefficient with leave-one-out cross validation (Q) of the model equation were 0.94 and 0.91, respectively. These results suggest that the concentrations of ingredients can explain most variances of inhibitory effects among brands. This model may be a useful method for the prediction of the GFJ interaction potential.

Topics: Antioxidants; Beverages; Citrus paradisi; Cytochrome P-450 CYP3A Inhibitors; Enzyme Inhibitors; Female; Flavanones; Food-Drug Interactions; Forecasting; Furocoumarins; Humans; In Vitro Techniques; Linear Models; Microsomes, Liver; Models, Statistical; Oxidation-Reduction; Testosterone

The effect of two varieties of grapefruit juice (white and ruby red) and its selected components (naringin, naringenin, and bergamottin) was investigated on the activity of the P-glycoprotein (P-gp) in male Sprague-Dawley rats. Talinolol, a nonmetabolized P-gp substrate, was used as a marker compound. The white grapefruit juice (GFJ) had a minor effect on talinolol pharmacokinetics, but the ruby red GFJ reduced the C max and the AUC (0-infinity) by 60% and 50% of the control, respectively. However, among the GFJ constituents tested, bergamottin (0.22 mg/kg) was the most potent component augmenting the C max and the AUC (0-infinity) of talinolol by 2.4- and 1.8-fold, respectively, if compared to the control group. The flavonoids naringenin (0.7 mg/kg) and naringin (2.4 and 9.4 mg/kg) had a similar effect increasing the talinolol C max and AUC (0-infinity) by 1.5- to 1.8-fold, respectively. In conclusion, the effect of GFJ on P-gp activity seems to depend on the variety, the concentration of compounds in the juice, and the composition of different ingredients.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Beverages; Biological Transport; Citrus paradisi; Flavanones; Fruit; Furocoumarins; Intestinal Mucosa; Male; Propanolamines; Rats; Rats, Sprague-Dawley; Species Specificity

To investigate the potential interaction between selected ingredients of grapefruit juice and, the transport of talinolol, a P-gp substrate, across Caco-2 cells monolayers was determined in the absence and presence of distinct concentrations of grapefruit juice, bergamottin, 6',7'-dihydroxybergamottin, 6',7'-epoxybergamottin, naringin, and naringenin. Talinolol permeability was selectively inhibited by grapefruit juice and its components. The furano coumarin, 6',7'-epoxybergamottin, was the most potent inhibitor (IC(50) = 0.7 microM), followed by 6',7'-dihydroxybergamottin (IC(50) = 34 microM) and bergamottin that did not show any inhibition at concentrations up to 10 microM. The flavonoid aglycone naringenin was around 10-fold more potent than its glycoside naringin with IC(50) values of 236 and 2409 microM, respectively. The flavonoids and furanocoumarins tested in this study are in the same range of concentration they are present in the juice contributing, therefore, for the overall inhibitory effect of GFJ on P-gp activity. The in vitro data suggest that compounds present in grapefruit juice are able to inhibit the P-gp activity modifying the disposition of drugs that are P-gp substrates such as talinolol.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Beverages; Caco-2 Cells; Citrus paradisi; Dose-Response Relationship, Drug; Flavanones; Food-Drug Interactions; Furocoumarins; Humans; Intestinal Absorption; Intestinal Mucosa; Membrane Transport Modulators; Permeability; Propanolamines

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.

Topics: Beverages; Chromatography, High Pressure Liquid; Citrus paradisi; Flavanones; Flavonoids; Furocoumarins

Grapefruit juice is responsible for many drug interactions but the exact components involved in this interaction are not precisely known. Flavonoids and furocoumarin derivatives such as naringenin and bergamottin, respectively, could be involved in the inhibition of drug metabolism. The objective of this paper is to investigate in vitro the possible metabolic hepatic interaction between simvastatin (SV) and bergamottin (BG) and thus to compare its effects to those of naringenin (NRG) the aglycone form of naringin (NR) (a flavonoid present in grapefruit juice). In human and rat microsomes and in rat hepatocytes, BG was found to be a mixed type inhibitor of SV metabolism. In rat liver microsomes the K(i) value of BG (K(i)=174+/-36 microM) is higher than the K(i) value of NRG (K(i)=29+/-11 microM). However, in human liver microsomes the K(i) values are similar in BG and NRG (K(i)=34+/-5 microM and 29+/-11 microM, respectively). Moreover, it seems that there is an interspecies difference between human and rat hepatic metabolism of SV involving different isoenzymes of CYP 450. In conclusion, our study shows that BG inhibits SV metabolism. BG and NRG could therefore be applied as markers in food-drug interaction studies in order to adjust posology.

Topics: Animals; Beverages; Citrus paradisi; Flavanones; Food-Drug Interactions; Furocoumarins; Hepatocytes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Liver; Microsomes, Liver; Rats; Simvastatin