Yoshiyuki Akiyama1, Naoya Matsumura2, Asami Ono3, Shun Hayashi4, Satoko Funaki5, Naomi Tamura5, Takahiro Kimoto6, Maiko Jiko7, Yuka Haruna7, Akiko Sarashina8, Masahiro Ishida8, Kotaro Nishiyama9, Masahiro Fushimi10, Yukiko Kojima10, Takuya Fujita11, Kiyohiko Sugano12. 1. Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. yoshiyuki.akiyama@jt.com. 2. Early Stage Oral Formulation Research & Development, Pharmaceutical Research & Development, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. 3. Laboratory for Chemistry, Manufacturing and Control Pharmaceuticals Production & Technology Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka, 410-2321, Japan. 4. Preclinical Research Unit, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugadenaka, Konohana-ku, Osaka, 554-0022, Japan. 5. DMPK & Analytical Sciences1, Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan. 6. Product Development Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. 7. Medical Analysis Research Department, Towa Pharmaceutical Co., Ltd., 134 Chudoji Minami-machi, Shimogyo-ku, Kyoto, 600-8813, Japan. 8. Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. 9. Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. 10. Biological Research Department, Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka, 532-0003, Japan. 11. Laboratory of Molecular Pharmacokinetics, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan. 12. Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan.
Abstract
PURPOSE: In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats. The purpose of the present study was to evaluate the predictability of the GUT framework for rat Fa. METHOD: The Fa values of 20 model drugs (a total of 39 Fa data) were predicted in a bottom-up manner. Based on the literature survey, the bile acid concentration (Cbile) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pKa, molecular weight, intrinsic solubility, bile micelle partition coefficients, and Caco-2 permeability were used as input data. RESULTS: The Fa values were appropriately predicted for highly soluble drugs (absolute average fold error (AAFE) = 1.65, 18 Fa data) and poorly soluble drugs (AAFE = 1.57, 21 Fa data). When the species difference in Cbile was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High Cbile in rats reduces the free fraction of drug molecules available for epithelial membrane permeation while increasing the solubility of poorly soluble drugs. CONCLUSION: The Fa values in rats were appropriately predicted by the GUT framework. This result would be of great help for a better understanding of species differences and model-informed preclinical formulation development.
PURPOSE: In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats. The purpose of the present study was to evaluate the predictability of the GUT framework for rat Fa. METHOD: The Fa values of 20 model drugs (a total of 39 Fa data) were predicted in a bottom-up manner. Based on the literature survey, the bile acid concentration (Cbile) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pKa, molecular weight, intrinsic solubility, bile micelle partition coefficients, and Caco-2 permeability were used as input data. RESULTS: The Fa values were appropriately predicted for highly soluble drugs (absolute average fold error (AAFE) = 1.65, 18 Fa data) and poorly soluble drugs (AAFE = 1.57, 21 Fa data). When the species difference in Cbile was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High Cbile in rats reduces the free fraction of drug molecules available for epithelial membrane permeation while increasing the solubility of poorly soluble drugs. CONCLUSION: The Fa values in rats were appropriately predicted by the GUT framework. This result would be of great help for a better understanding of species differences and model-informed preclinical formulation development.