Effects of orange juice on the pharmacokinetics of atenolol

Lilja, Jari J.; Raaska, Kari; Neuvonen, Pertti J.

doi:10.1007/s00228-005-0930-9

Cited by 85 publications

(67 citation statements)

References 21 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: 82%

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: 82%

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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“…Orange juice contains minor amounts of furanocoumarins and has little CYP3A4 inhibitory effect Won et al, 2010). It has been demonstrated that orange juice reduces the AUC of celiprolol (Lilja et al, 2004), atenolol (Lilja et al, 2005), fexofenadine (Dresser et al, 2002), ciprofloxacin (Neuhofel et al, 2002), and levofloxacin (Wallace et al, 2003). Because at least some of these drugs (e.g., fexofenadine, celiprolol) have been identified as substrates of OATPs expressed in the intestine, uptake inhibition of these transporters may be the cause for these interactions.…”

Section: Drug-food Interactionsmentioning

confidence: 99%

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

2013

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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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Effects of orange juice on the pharmacokinetics of atenolol

Abstract: Orange juice moderately interferes with the gastrointestinal absorption of atenolol. This food-drug interaction can be of clinical significance.

Cited by 85 publications

References 21 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

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

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

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