Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range
Open accessAbstract
Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input parameter for oral exposure prediction of compounds with limited solubility. Biorelevant media of the fasted and fed state have been published for humans, as well as for dogs in the fasted state. In a drug discovery environment, rodents are the most common animal model to assess the oral exposure of drug candidates. In this study a rat simulated intestinal fluid (rSIF) is proposed as a more physiologically relevant media to describe drug solubility in rats. Equilibrium solubility in this medium was tested as input parameter for physiologically-based pharmacokinetics (PBPK) simulations of oral pharmacokinetics in the rat. Simulations were compared to those obtained using other solubility values as input parameters, like buffer at pH 6.8, human simulated intestinal fluid and a comprehensive dissolution assay based on rSIF. Our study on nine different compounds demonstrates that the incorporation of rSIF equilibrium solubility values into PBPK models of oral drug exposure can significantly improve the reliability of simulations in rats for doses up to 300 mg/kg compared to other media. The comprehensive dissolution assay may help to improve further simulation outcome, but the greater experimental effort as compared to equilibrium solubility may limit its use in a drug discovery environment. Overall, PBPK simulations based on solubility in the proposed rSIF medium can improve prioritizing compounds in drug discovery as well as planning dose escalation studies, e.g. during toxicological investigations.
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Rat simulated intestinal fluid (rSIF) was prepared according to Berghausen et al. who concluded that the incorporation of rSIF equilibrium solubility values into in silico models of oral drug exposure can significantly improve the accuracy of simulations in rats for doses up to 300 mg/kg compared to other media.
“Rat simulated intestinal fluid (rSIF) was prepared according to Berghausen et al. who investigating nine compounds with different physico-chemical properties and concluded that the incorporation of rSIF equilibrium solubility values into in silico models of oral drug exposure can significantly improve the accuracy of simulations in rats for doses up to 300 mg/kg compared to other media (Berghausen”
From Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across PermeapadⓇ membrane and in vivo absorption (2020) · cites this paper as Berghausen et al., 2016
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- Authors
- Berghausen, J., Seiler, F. H., Gobeau, N., & Faller, B.
- Affiliations
- Novartis (Switzerland) (CH)
- ORCID
- Gobeau, Nathalie
- Venue
- ADMET & DMPK
- Published
- 2016-03-30
- Volume
- 4
- Issue
- 1
- Pages
- 35
- ISSN
- 1848-7718 (ISSN-L)
- OpenAlex
- W2316567121
- Cited by
- 14
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2018: 2 · 2017: 1 · 2016: 1
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- ADMET & DMPK (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Zagreb University Computing Centre (SRCE) (submittedVersion, other-oa)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- equilibrium solubility, physiologically based pharmacokinetic modeling, oral pharmacokinetics, biorelevant media, dose escalation, drug discovery, toxicology
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