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Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans

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Abstract

Background and Objective

Oral bioavailability (F) is one of the key factors that need to be determined in drug discovery. This factor is determined by the permeability and solubility of new molecule entities (NMEs) according to the biopharmaceutics classification system (BCS).

Methods

In the present study, we evaluated the permeability of 22 drugs in rat intestinal tissues using an Ussing chamber system and correlated the permeability with data on human intestinal absorption (Fa) and intestinal availability (Fa × Fg) reported in the literature.

Results

The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (Fa) and the fraction escaping intestinal metabolism (Fg) than Fa itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal Papp was generally higher than that in other segments. Finally, the function of the efflux transporter P-glycoprotein (P-gp) with regard to oral absorption of substrates was evaluated with an Ussing chamber. We also demonstrated that the rat intestinal stability of the three cytochrome P450 (CYP) substrates was consistent with the human data.

Conclusion

An Ussing chamber system incorporating rat intestinal tissue would be a valuable tool to predict human intestinal absorption and metabolism for molecules with various physicochemical properties.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics (DMPK) Department, Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing, 100176, China

    Chi Guan, Yingxin Yang, Dong Tian, Zhiqiang Jiang, Huiying Zhang, Yali Li, Jiaxiu Yan, Congman Zhang, Chun Chen, Junhua Zhang, Jing Wang, Yu Wang, Hongwen Du, Hongyu Zhou & Tao Wang

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  1. Chi Guan
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  2. Yingxin Yang
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  3. Dong Tian
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  12. Yu Wang
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  15. Tao Wang
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Corresponding author

Correspondence to Tao Wang.

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Funding

The trials were supported by (DMPK) Department, Pharmaron, Beijing, China.

Conflict of Interest

Authors have no conflicts of interest to declare.

Ethics Approval

All studies were approved by Pharmaron’s Institutional Animal Care and Use Committee (IACUC). All procedures and the care of the rats were in accordance with the National Guidelines for Experimental Animal Welfare (MOST, China, 2006) at the Center for Animal Experiments, which has full accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care International. Maximum effort was exerted to minimize animal suffering and the number of animals necessary for the attainment of reliable data.

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Not applicable.

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Not applicable.

Data Availability Statement

Data supporting the findings are available from the corresponding author upon request.

Code Availability

The proprietary software program GraphPad was used for the analysis reported here.

Author Contributions

C.G., D.T., Y.X.Y., and T.W. contributed to interpretation of the results as well as drafting and revising the manuscript, and agree to be accountable for all aspects of the work. J.H.Z., J.W., Y.W., and J.Y. contributed to data analysis. T.W., H.Y.Z., H.W.D., C.G., Y.X.Y., Z.Q.J., H.Y.Z., Y.L.L., J.X.Y., C.M.Z., and C.C. contributed to planning, design, and data collection of this analysis.

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Guan, C., Yang, Y., Tian, D. et al. Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans. Eur J Drug Metab Pharmacokinet 47, 639–652 (2022). https://doi.org/10.1007/s13318-022-00780-x

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