Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans

Metry, Melissa; Krug, Samuel A.; Karra, Vijaya Kumari; Ekins, Sean; Hoag, Stephen W.; Kane, Maureen A.; Fink, Jeffrey C.; Polli, James E.

doi:10.1007/s11095-022-03312-z

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…Increasing permeability to this value had no impact on the modeling results (data not shown) due to the fact that P app was not the rate-limiting step. In addition to P-gp and OATP, the human intestine expresses several other transporters, many of which are important for drug disposition, e.g., human peptide transporter 1 and the apical sodium-dependent bile acid transporter. ,, Species differences in the transporter protein activity, substrate specificity, and expression levels can be vast and cannot be ignored . Additional in vitro experiments are needed to quantify the impact of the excipient type and concentration on the kinetics of intestinal drug transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have reported that feeding times post oral dosing can alter stomach emptying and therefore absorption profiles in rodents . Another variable in oral absorption is the presence of high concentrations of excipients in oral formulations, which have traditionally been considered inert. , However, a number of reports have highlighted the inhibitory effect of commonly used formulation excipients on intestinal transporters with in vitro or animal models. − The impact of excipients on human intestinal transporters is less well-understood. , There is a critical need from a regulatory perspective to understand the impact of excipients on drug absorption. , In order to extend the continuous model for prediction of the excipient impact on transporters, the present work used glyburide (GLY) as a model drug with varying formulations in a rat model.…”

Section: Introductionmentioning

confidence: 99%

“…22−24 The impact of excipients on human intestinal transporters is less wellunderstood. 10,25 There is a critical need from a regulatory perspective to understand the impact of excipients on drug absorption. 20,21 In order to extend the continuous model for prediction of the excipient impact on transporters, the present work used glyburide (GLY) as a model drug with varying formulations in a rat model.…”

Section: ■ Introductionmentioning

confidence: 99%

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The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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Oral drug absorption is known to be impacted by the physicochemical properties of drugs, properties of oral formulations, and physiological characteristics of the intestine. The goal of the present study was to develop a mathematical model to predict the impact of particle size, feeding time, and intestinal transporter activity on oral absorption. A previously published rat continuous intestine absorption model was extended for solid drug absorption. The impact of active pharmaceutical ingredient particle size was evaluated with glyburide (GLY) as a model drug. Two particle size suspensions of glyburide were prepared with average particle sizes of 42.7 and 4.1 μm. Each suspension was dosed as a single oral gavage to male Sprague Dawley rats, and concentration–time (C–t) profiles of glyburide were measured with liquid chromatography coupled with tandem mass spectrometry. A continuous rat intestine absorption model was extended to include drug dissolution and was used to predict the absorption kinetics of GLY depending on particle size. Additional literature datasets of rat GLY formulations with particle sizes ranging from 0.25 to 4.0 μm were used for model predictions. The model predicted reasonably well the absorption profiles of GLY based on varying particle size and varying feeding time. The model predicted inhibition of intestinal uptake or efflux transporters depending on the datasets. The three datasets used formulations with different excipients, which may impact the transporter activity. Model simulations indicated that the model provides a facile framework to predict the impact of transporter inhibition on drug C–t profiles. Model simulations can also be conducted to evaluate the impact of an altered intestinal lumen environment. In conclusion, the rat continuous intestine absorption model may provide a useful tool to predict the impact of varying drug formulations on rat oral absorption profiles.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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“…Bile acid measurements were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described ( 27 , 28 , 29 ). Briefly, 100 μl of plasma were loaded directly onto the ISOLUTE PLD+ column per manufacturer’s instructions, and 5 μl of internal standard (1 μg/ml deuterated bile acids stock) was added to each tube.…”

Section: Methodsmentioning

confidence: 99%

“…LC-MS/MS analysis was performed according to previously published methodology on a Waters I-Class ultra performance liquid chromatography coupled to a Waters TQ-XS tandem quadrupole mass spectrometer with LC-MS/MS conditions summarized in supplemental Table S2 ( 28 ). Expected retention time and LC-MS/MS acquisition parameters for each individual analyte in the three timed multiple reaction monitoring (MRM) segments are given in supplemental Table S3 .…”

Section: Methodsmentioning

confidence: 99%