Comparison of Inhibitory Duration of Grapefruit Juice on Organic Anion-Transporting Polypeptide and Cytochrome P450 3A4

Abstract

Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (C max ) and the area under the plasma concentration-time curve from 0 to 8 h (AUC 0-8 ) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The C max and AUC 0-8 returned to the control levels on days 3 and 7. In contrast, AUC 0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC 0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.Key words organic anion-transporting polypeptide; cytochrome P450; grapefruit juice Food and medication are often taken together. However, certain foods interact with drugs by altering mechanisms that are important determinants of systemic drug availability. In particular, grapefruit juice is known to alter the pharmacokinetics of over 30 prescription drugs by affecting their bioavailability.1-3) The mechanism of this interaction is inhibition of intestinal cytochrome P450 (CYP) 3A4 activity and increased systemic exposure of CYP3A4 substrates. [4][5][6][7][8] In 2012, the United States Food and Drug Administration issued a press release to warn consumers that the intake of grapefruit juice along with medication could cause dangerous side effects. 9)Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of the organic anion-transporting polypeptide (OATP) uptake transporter, which is a family of membrane solute carrier (SLC) transporters. OATP influences the intestinal absorption of several drugs in clinical use. [10][11][12][13][14] Grapefruit juice decreases the plasma concentrations of some drugs including β-adrenoceptor blocking agents and antihistamines by this mechanism. For example, grapefruit juice was reported to reduce the area under the plasma concentration-time curve (AUC) value for fexofenadine to a mean value of 58% of that when the drug was administered with the corresponding volume of water.10) Furthermore, celiprolol, ...

Fruit Juice in Infants, Children, and Adolescents: Current Recommendations

“…8 -12 Although the ingestion of grapefruit juice has been shown to reduce the activity of intestinal cytochrome P450 3A4 (CYP3A4) and produce potential drug-nutrient interactions (eg, increased bioavailability) of drugs that are CYP3A4 substrates (eg, cyclosporine, tacrolimus, atorvastatin, felodipine, fexofenadine, specific antiretroviral agents), recent evidence suggests that grapefruit juice can also inhibit organic acid transporter activity. 9 In addition to grapefruit juice, flavonoids present in oranges and apples have also been shown to reduce the activity of the organic acid transporter OATP2B1. 8 Although the grapefruit juice-CYP3A4 substrate interaction and the potential for producing significant nutrient-drug interactions is the most well characterized, it should be noted that, in addition to inhibiting CYP3A4 activity, cranberry, pomegranate, and blueberry juice can inhibit the activity of CYP2C9, 10,12 a cytochrome P450 isoform that catalyzes the biotransformation of therapeutic drugs such as ibuprofen, flurbiprofen, warfarin, phenytoin, fluvastatin, and amitriptyline.…”

“…10 In evaluating the potential juice-drug interactions, the coadministration of fruit juice and a drug for which metabolism or transport could be affected by a flavonoid should not be considered immediately as a contraindication for treatment. The amount and type of juice being ingested, 9 specific information characterizing a given interaction, and whether the drug(s) being taken has a low (eg, antiretrovirals, calcineurin inhibitors, calcium channel blockers, warfarin) or high therapeutic index must be considered in the evaluation of a potential interaction. Consultation between the physician and pharmacist can be beneficial in considering the potential clinical significance of a juice-drug interaction.…”

Inhibitory effects of dioscin on cytochrome P450 enzymes

“…28 The grapefruit is a textbook example of a CYP3A4 inhibitor, and the grapefruit juice-mediated CYP3A4 reaction plays an important role in organic anion-transporting polypeptide (OATP) metabolism. 29 The Lineweaver-Burk plots of inhibitory kinetic data in this paper showed that dioscin is a potent and reversible competitive inhibitor of CYP3A4, with K i ¼ 15.5 mM (Fig. 4C).…”

Enzyme‐ and transporter‐mediated beverage–drug interactions: An update on fruit juices and green tea

“…Regarding duration of activity of GFJ on OATP, Kim and colleagues reported that consumption of GFJ concomitantly or 2 hours before fexofenadine administration was associated with reduced oral fexofenadine plasma concentrations, whereas fexofenadine exposure was not affected when GFJ was taken 4 hours before drug administration . Recently, Tanaka et al compared the inhibitory duration of GFJ on celiprolol (an OATP substrate) and midazolam (a CYP3A substrate) in healthy volunteers, and their results also indicated that GFJ inhibition on OATP appears to dissipate over a shorter period than has been observed with CYP3A inhibition . In addition to the inhibitory duration of GFJ on OATP, the effect of GFJ volume on OATP inhibition was also evaluated .…”