Apple juice greatly reduces systemic exposure to atenolol

Jeon, Hyewon; Jang, In Jin; Lee, Seung Hwan; Ohashi, Kyoichi; Kotegawa, Tsutomu; Ieiri, Ichiro; Cho, Joo Youn; Yoon, Seo Hyun; Shin, Sang Goo; Yu, Kyung‐Sang; Lim, Kyoung Soo

doi:10.1111/j.1365-2125.2012.04324.x

Cited by 66 publications

(68 citation statements)

References 36 publications

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“…In contrast to FJ-drug interactions involving CYP3A substrates, decreased bioavailability of OATP2B1 substrates was observed with not only GFJ, but also OJ and AJ (Dresser et al, 2002;Lilja et al, 2004Lilja et al, , 2005Imanaga et al, 2011;Tapaninen et al, 2011;Jeon et al, 2013). Naringin, the main constituent flavonoid of GFJ, is thought to be a major inhibitor of OATP2B1-mediated drug transport in GFJ Shirasaka et al, 2009Shirasaka et al, , 2010aShirasaka et al, , b, 2011aShirasaka et al, , b, 2013 that in GFJ, it is unlikely that naringin is a major contributor to OATP2B1-mediated drug interactions involving OJ and AJ (Ameer et al, 1996;Ho et al, 2000).…”

Section: Introductionmentioning

confidence: 85%

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

et al. 2012

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Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP)2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process. Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro. When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC 50 = 1.5%). A similar but less potent effect was observed with OJ (IC 50 = 21%), whereas GFJ had no effect. Similar results were obtained in preincubation studies using fexofenadine. Preincubation with OJ and AJ resulted in timedependent inhibition of OATP2B1. Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake. Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively. Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ. Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect. Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined.

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Section: Introductionmentioning

confidence: 85%

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

et al. 2012

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“…Despite its very poor permeability, atenolol has a moderate oral bioavailability at 50% (Kirch and Gorg, 1982). It is also reported that the systemic exposure to atenolol is markedly reduced by apple juice ingestion, a phenomenon attributed to the inhibition of intestinal OATP2B1 by constituents present in apple juice (Jeon et al, 2013). It is possible that a system possessing more in vivo-like expression of uptake transporters could help serve as a useful tool in preventing the needless abandonment of compounds with poor passive permeability, but that would still have sufficient bioavailability in vivo.…”

Section: Downloaded Frommentioning

confidence: 99%

Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism

Yamaura

Chapron

Wang

et al. 2015

Drug Metabolism and Disposition

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To further the development of a model for simultaneously assessing intestinal absorption and first-pass metabolism in vitro, Caco-2, LS180, T84, and fetal human small intestinal epithelial cells (fSIECs) were cultured on permeable inserts, and the integrity of cell monolayers, CYP3A4 activity, and the inducibility of enzymes and transporters involved in intestinal drug disposition were measured. Caco-2, T84, and fSIECs all formed tight junctions, as assessed by immunofluorescence microscopy for zonula occludens-1, which was well organized into circumscribing strands in T84, Caco-2, and fSIECs but was diffuse in LS180 cells. The transepithelial electrical resistance value for LS180 monolayers was lower than that for Caco-2, T84, and fSIECs. In addition, the apical-to-basolateral permeability of the paracellular marker Lucifer yellow across LS180 monolayers was greater than in fSIECs, T84, and Caco-2 monolayers. The transcellular marker propranolol exhibited similar permeability across all cells. With regard to metabolic capacity, T84 and LS180 cells showed comparable basal midazolam hydroxylation activity and was inducible by rifampin and 1a,25(OH) 2 D 3 in LS180 cells, but only marginally so in T84 cells. The basal CYP3A4 activity of fSIECs and Caco-2 cells was much lower and not inducible. Interestingly, some of the drug transporters expressed in LS180 and Caco-2 cells were induced by either 1a,25(OH) 2 D 3 or rifampin or both, but effects were limited in the other two cell lines. These results suggest that none of the cell lines tested fully replicated the drug disposition properties of the small intestine and that the search for an ideal screening tool must continue.

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“…Atenolol was previously shown to be a substrate of the hOAT polypeptide 1A2 (Kato et al, 2009). Intestinal organic anion transporting polypeptides (OATPs) are thought to play a role in atenolol oral absorption, and inhibition of intestinal OATPs by fruit juices has been proposed as the underlying mechanism of atenolol-fruit juice interactions in humans (Lilja et al, 2005;Jeon et al, 2013). In addition, there is also evidence that atenolol may be transported by the drug efflux transporter P-glycoprotein (P-gp) (Augustijns and Mols, 2004;Wang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

et al. 2015

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Atenolol is a b-blocker widely used in the treatment of hypertension. Atenolol is cleared predominantly by the kidney by both glomerular filtration and active secretion, but the molecular mechanisms involved in its renal secretion are unclear. Using a panel of human embryonic kidney cell lines stably expressing human organic cation transporter (hOCT) 1-3, human organic anion transporter (hOAT) 1, hOAT3, human multidrug and toxin extrusion protein (hMATE) 1, and hMATE2-K, we found that atenolol interacted with both organic cation and anion transporters. However, it is transported by hOCT1, hOCT2, hMATE1, and hMATE2-K, but not by hOCT3, hOAT1, and hOAT3. A detailed kinetic analysis coupled with absolute quantification of membrane transporter proteins by liquid chromatographytandem mass spectrometry revealed that atenolol is an excellent substrate for the renal transporters hOCT2, hMATE1, and hMATE2-K. The K m values for hOCT2, hMATE1, and hMATE2-K are 280 6 4, 32 6 5, and 76 6 14 mM, respectively, and the calculated turnover numbers are 2.76, 0.41, and 2.20 s 21 , respectively. To demonstrate unidirectional transepithelial transport of atenolol, we developed and functionally validated a hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cell culture model. Transwell studies showed that atenolol transport in the basal (B)-to-apical (A) direction is 27-fold higher than in the A-to-B direction, whereas its B-to-A/A-to-B transport ratio was only 2 in the vectortransfected control cells. The overall permeability of atenolol in the B-to-A direction in hOCT2/hMATE1 cells was 44-fold higher than in control cells. Together, our data support that atenolol tubular secretion is mediated through the hOCT2/hMATEs secretion pathway and suggest a significant role of organic cation transporters in the disposition of an important antihypertensive drug.

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Apple juice greatly reduces systemic exposure to atenolol

Cited by 66 publications

References 36 publications

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

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