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Rate-Limiting Steps of Oral Absorption for Poorly Water-Soluble Drugs in Dogs; Prediction from a Miniscale Dissolution Test and a Physiologically-Based Computer Simulation

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ABSTRACT

Purpose

Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility–high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption.

Methods

Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption.

Results

The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption.

Conclusion

The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.

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ACKNOWLEDGMENTS

We would like to express our gratitude to Mr. Tessai Yamamoto for his helpful contribution to the plasma concentration analysis, Dr. Motohiro Kato for his help in the deconvolution analysis, Ms Atsuko Higashida for her help in the Caco-2 experiments, the pharmaceutical profiling group members for their help with the in vivo experiments, and Mr. Shoichi Higo for his helpful comments and suggestions.

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Authors and Affiliations

  1. Discovery Platform Technology Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan

    Ryusuke Takano, Kentaro Furumoto, Koji Shiraki & Noriyuki Takata

  2. Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan

    Yoshiki Hayashi & Yoshinori Aso

  3. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan

    Shinji Yamashita

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  1. Ryusuke Takano
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  2. Kentaro Furumoto
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Correspondence to Ryusuke Takano.

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Takano, R., Furumoto, K., Shiraki, K. et al. Rate-Limiting Steps of Oral Absorption for Poorly Water-Soluble Drugs in Dogs; Prediction from a Miniscale Dissolution Test and a Physiologically-Based Computer Simulation. Pharm Res 25, 2334–2344 (2008). https://doi.org/10.1007/s11095-008-9637-9

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