Prediction of Oral Absorption of Low-Solubility Drugs by Using Rat Simulated Gastrointestinal Fluids: The Importance of Regional Differences in Membrane Permeability and Solubility

Abstract

-Purpose. This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. Methods. Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. Results. The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. Conclusion. These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development.

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats

“…For both fasted and fed conditions, several fluid compositions have been suggested as biorelevant media to simulate conditions in the human GI tract, and hence, improve IVIVC [9][10][11]. Multiple biorelevant media are also commercially available, based on the composition of GI fluids in humans and dogs [12]. However, since the composition of the GI fluids vary greatly between species, it is challenging to obtain good IVIVC for in vivo studies performed in commonly used laboratory animals, e.g.…”

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

“…When applied in a project to a chemical scaffold which had several BCS class 2 compounds with low solubility, in buffer and in human FASSIF, we decided to measure the solubility in a medium with increased bile salt content aimed at better mimicking the content of the intestinal fluid in rats (34,35). It was done for eight compounds, four for which C max was under-predicted by more than a factor 3 and four for which C max was within 2 fold of the observations.…”

Considerations for the development of in vitro dissolution tests to reduce or replace preclinical oral absorption studies

“…Bile reflux is known to occur in the rat and hence a bile salt concentration of 4mM is suggested based on the physiological values (Tanaka et al, 2014). Sodium taurodeoxycholate was not found to be in significant quantities in the rat bile duct, therefore only sodium taurocholate was selected (Alvaro et al, 1986).…”

“…Modification of a medium already published in the literature is suggested based on the physiological values. A medium to simulate the rats' intestinal fluid in the fasted state has been proposed by Tanaka et al (2014). The first modification proposed refers to the pH of the medium.…”

“…The first modification proposed refers to the pH of the medium. Based on the median value of the pH of the rats intestinal fluids in the fasted state (Table 2) a modification from pH 7.0 (value based on measurements at 10-15 min intervals over 75 min after administration of 1mL ultrapure water) (Tanaka et al, 2014) to pH 6.0 is proposed. 0.2 M sodium dihydrogen phosphate, 0.2 M acetic acid and 0.2 M sodium hydroxide are suggested as the buffer system for the desired pH value (pH 6.0).…”