Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Berghausen, Joerg; Seiler, Frank H.; Gobeau, Nathalie; Faller, Bernard

doi:10.5599/admet.4.1.258

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…To assess precipitation and pH upon dilution in rat intestinal fluid, formulations were diluted with a modified rat simulated intestinal fluid (rSIF) based on the rSIF reported by Berghausen et al (2016) . The modified rSIF contained 25 mM sodium taurocholate, 5.16 mM lecithin, 30 mM maleic acid, 19 mM NaCl and was adjusted to pH 6.0 with NaOH.…”

Section: Methodsmentioning

confidence: 99%

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Nielsen

Holm

Pijpers

et al. 2021

International Journal of Pharmaceutics: X

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P-glycoprotein inhibitors, like zosuquidar, have widely been used to study the role of P-glycoprotein in oral absorption. Still, systematic studies on the inhibitor dose-response relationship on intestinal drug permeation are lacking. In the present study, we investigated the effect of 0.79 nM-2.5 μM zosuquidar on etoposide permeability across Caco-2 cell monolayers. We also investigated etoposide pharmacokinetics after oral or IV administration to Sprague Dawley rats with co-administration of 0.063–63 mg/kg zosuquidar, as well as the pharmacokinetics of zosuquidar itself. Oral zosuquidar bioavailability was 2.6–4.2%, while oral etoposide bioavailability was 5.5 ± 0.9%, which increased with increasing zosuquidar doses to 35 ± 5%. The intestinal zosuquidar concentration required to induce a half-maximal increase in bioavailability was estimated to 180 μM. In contrast, the IC 50 of zosuquidar on etoposide permeability in vitro was only 5–10 nM, and a substantial in vitro-in vivo discrepancy of at least four orders of magnitude was thereby identified. Overall, the present study provides valuable insights for future formulation development that applies fixed dose combinations of P-glycoprotein inhibitors to increase the absorption of poorly permeable P-glycoprotein substrate drugs.

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Section: Methodsmentioning

confidence: 99%

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Nielsen

Holm

Pijpers

et al. 2021

International Journal of Pharmaceutics: X

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“…Using these refined input parameters helped to further improve the predictions. However the experiment being relatively labor intensive, it is not practical in the compound optimization phase (37). Another possible reason for which BCS class 2 compounds may not be well predicted is the lack of information on the dissolution or precipitation rate.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

et al. 2016

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The generic GastroPlus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses and understand oral absorption.

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“…It should be noted that there are simulated small intestinal fluids reported for rats [119]; dogs [120] and pigs [121].…”

Section: Small Intestinal Contentsmentioning

confidence: 99%

In vivo models to evaluate ingestible devices: Present status and current trends

Stamatopoulos

O’Farrell

Simmons

et al. 2021

Advanced Drug Delivery Reviews

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Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Abstract: Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input

Cited by 10 publications

References 20 publications

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

In vivo models to evaluate ingestible devices: Present status and current trends

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