Prediction of Oral Drug Absorption in Rats from In Vitro Data

Yoshiyuki Akiyama; Naoya Matsumura; Asami Ono; Shun Hayashi; Satoko Funaki; Naomi Tamura; Takahiro Kimoto; Maiko Jiko; Yuka Haruna; Akiko Sarashina; Masahiro Ishida; Kotaro Nishiyama; Masahiro Fushimi; Yukiko Kojima; Takuya Fujita; Kiyohiko Sugano

doi:10.1007/s11095-022-03173-6

Prediction of Oral Drug Absorption in Rats from In Vitro Data

Pharm Res. 2023 Feb;40(2):359-373. doi: 10.1007/s11095-022-03173-6. Epub 2022 Feb 15.

Authors

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

Affiliations

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.

PMID: 35169960
DOI: 10.1007/s11095-022-03173-6

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 (C_bile) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pK_a, 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 C_bile was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High C_bile 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.

Keywords: Oral absorption; mechanistic modeling; physicochemical properties; species differences.

MeSH terms

Administration, Oral
Animals
Bile*
Caco-2 Cells
Dogs
Drug Discovery
Humans
Intestinal Absorption*
Permeability
Rats
Solubility