Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats

Funai, Yuta; Shirasaka, Yoshiyuki; Ishihara, Marika; Takemura, Motohide; Ichijo, Kazuki; Kishimoto, Hisanao; Inoue, Katsuhisa

doi:10.1124/dmd.118.084483

Cited by 23 publications

(24 citation statements)

References 24 publications

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“…It is interesting that rOATP1A5 and human OCT1 are inhibited by fruit juice flavonoids (Dresser et al, 2002;Mimura et al, 2015). The possibility remains that alterations in intestinal water movement caused by the high osmolarities of the AJ and GFJ vehicles used in this study (2794 and 2464 mOsm/kg, respectively) have affected fexofenadine absorption in a similar fashion as was observed for the atenolol-AJ interaction in rats (Funai et al, 2019).…”

Section: Discussionsupporting

confidence: 52%

“…For instance, there are some poorly metabolized OATP2B1 substrates such as rosuvastatin and pravastatin that are not subject to significantly reduced oral absorption when taken together with fruit juices in clinical studies (Lilja et al, 1999;Kashihara et al, 2017). Additionally, a recent study showed that the major clinical drug interaction between atenolol and apple juice is not related to OATP2B1 since the drug is not a substrate and osmolarity may be a contributing factor (Funai et al, 2019). Another potentially disconcerting observation are reports that show that OATP2B1 is localized to the basolateral (Mooij et al, 2016;Keiser et al, 2017) rather than the apical (luminal) membrane of enterocytes (Kobayashi et al, 2003), casting doubt on a role in oral drug absorption and fooddrug interactions.…”

Section: Introductionmentioning

confidence: 99%

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Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Medwid

Knauer

et al. 2019

Drug Metab Dispos

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Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the Slco2b1 gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wildtype (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC 0-last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced C max by 80% and 88%, respectively, while the AUC 0-last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine C max and AUC 0-last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Medwid

Knauer

et al. 2019

Drug Metab Dispos

View full text Add to dashboard Cite

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“…Solution osmolality influences gut‐lumen fluid volume, which then alters drug concentration and impacts absorption by decreasing the concentration gradient, especially for low‐permeability compounds 59 . For example, administering atenolol with apple juice (∼750 mOsm/kg) results in a 63% decrease in bioavailability compared with administering the drug with purified water 59 . This may, in part, be a function of apple juice's ability to inhibit a specific transporter involved in atenolol absorption 54…”

Section: Influence Of Nutrition Interactionsmentioning

confidence: 99%

“…Aside from pharmacokinetic interactions at transporters/enzymes caused by food components, the characteristics of fluid intake may alter drug bioavailability. Solution osmolality influences gut‐lumen fluid volume, which then alters drug concentration and impacts absorption by decreasing the concentration gradient, especially for low‐permeability compounds 59 . For example, administering atenolol with apple juice (∼750 mOsm/kg) results in a 63% decrease in bioavailability compared with administering the drug with purified water 59 .…”

Section: Influence Of Nutrition Interactionsmentioning

confidence: 99%

Enteral Medication for the Tube‐Fed Patient: Making This Route Safe and Effective

Boullata

2020

Nut in Clin Prac

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The administration of medication through an enteral access device requires important forethought. Meeting a patient's therapeutic needs requires achieving expected drug bioavailability without increasing the risk for toxicity, therapeutic failure, or feeding tube occlusion. Superimposing gut dysfunction, critical illness, or enteral nutrition–drug interaction further increases the need for a systematic approach to prescribing, evaluating, and preparing a drug for administration through an enteral access device. This review will explain the fundamental factors involved in drug bioavailability through the gut, address the influencing considerations for the enterally fed patient, and describe best practices for enteral drug preparation and administration.

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“…Specifically, the fraction absorbed of atenolol (a low-permeability drug) was significantly greater when administered in purified water than when administered in isosmotic solution, while there was no significant difference in the fraction absorbed of antipyrine (a high-permeability drug). We also showed that the high-osmolality environment in the GI tract resulting from oral ingestion of apple juice induces secretion of water into the lumen, resulting in a reduction of luminal concentration and decreased absorption of coadministered atenolol [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Influence of osmolality on gastrointestinal fluid volume and drug absorption: potential impact on oral salt supplementation

Takemura

Tanaka

Inoue

et al. 2021

J Pharm Health Care Sci

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Background The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most frequent cause of hyponatremia in patients with cerebrovascular disease, and is often treated with oral salt tablets. However, we have shown that osmolality-dependent variations in gastrointestinal (GI) fluid volume can alter the concentration of a poorly permeable drug in the GI tract, potentially affecting its absorption. Here, we examined the effect of ingestion of hyperosmotic solution (10% NaCl) on drug concentration and absorption in the GI tract. Methods The effects of osmolality on luminal fluid volume and drug absorption in rat intestine (jejunum, ileum and colon) were examined by means of an in situ closed loop method using fluorescein isothiocyanate-dextran 4000 (FD-4) and atenolol. In vivo absorption in rats was determined by measuring the plasma concentration after oral administration of the test compounds dissolved in purified water or hyperosmotic solution (10% NaCl). Results Administration of hyperosmotic solution directly into the GI tract significantly increased the GI fluid volume, owing to secretion of water into the lumen. After administration in hyperosmotic solution, the luminal concentration of non-permeable FD-4 was significantly lower than the initial dosing concentration, whereas after administration in purified water, the luminal concentration exceeded the initial concentration. The fraction absorbed of atenolol was markedly lower after administration in hyperosmotic solution than after administration in purified water. An in vivo pharmacokinetic study in rats was consistent with these findings. Conclusions Administration of hyperosmotic NaCl solution increased GI fluid volume and reduced the plasma level of orally administered atenolol. This may imply that oral salt tablets used to treat hyponatremia in SIADH patients could decrease the intestinal absorption of concomitantly administered drugs, resulting in lower plasma exposure.

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Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats

Cited by 23 publications

References 24 publications

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Enteral Medication for the Tube‐Fed Patient: Making This Route Safe and Effective

Influence of osmolality on gastrointestinal fluid volume and drug absorption: potential impact on oral salt supplementation

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