Decrease in gastrointestinal absorption of roxithromycin in bile duct cannulated rats due to depletion of bile salts

Lee, Juhyun; Park, Young Ju; Oh, Ju‐Hee; Lee, Young‐Joo

doi:10.1002/bdd.1845

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…[6] The importance of macrolide antibiotics uptake by bile has also been confirmed by experiments with bile duct cannulated rats, which showed significantly reduced plasma concentrations of roxithromycin. [7] The use of macrolide antibiotics has been reported as the cause for several diseases related to the biliary system. For example, azithromycin- or erythromycin-induced cholestasis is believed to result from hypersensitivity towards these drugs and causes lesions of canalicular membranes, which could lead to vanishing bile-duct syndrome.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

Glanzer

Pulido

Tutz

et al. 2015

Chemistry A European J

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Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50) values.

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Section: Introductionmentioning

confidence: 99%

Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

Glanzer

Pulido

Tutz

et al. 2015

Chemistry A European J

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Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

Takahashi¹,

Chang²,

Pang³

et al. 2019

DML

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Background: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study. Method: High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK. Results: The enrichment of 14C, which resulted in higher specific activities, was consistent with faster and more extensive absorption of the radiotracer from the dosing formulation. This resulted in overestimating the dose absorbed, the extent of elimination in urine and bile, and the exposures to circulating metabolites. These biases were corrected by the specific activities determined for study samples by mass spectrometry. Conclusion: Assuming that the radiotracer was proportional to total drug throughout a radiolabeled study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing the differential absorption of the radiotracer.

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Decrease in gastrointestinal absorption of roxithromycin in bile duct cannulated rats due to depletion of bile salts

Cited by 2 publications

References 22 publications

Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

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