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Effect of Excessive Serotonin on Pharmacokinetics of Cephalexin after Oral Administration: Studies with Serotonin-Excessive Model Rats

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Abstract

Purpose

Serotonin (5-HT) is important for gastrointestinal functions, but its role in drug absorption remains to be clarified. Therefore, the pharmacokinetics and oral absorption of cephalexin (CEX) were examined under 5-HT-excessive condition to understand the role of 5-HT.

Methods

5-HT-excessive rats were prepared by multiple intraperitoneal dosing of 5-HT and clorgyline, an inhibitor for 5-HT metabolism, and utilized to examine the pharmacokinetics, absorption behavior and the intestinal permeability for CEX.

Results

Higher levels of 5-HT in brain, plasma and small intestines were recognized in 5-HT-excessive rats, where the oral bioavailability of CEX was significantly enhanced. The intestinal mucosal transport via passive diffusion of CEX was significantly increased, while its transport via PEPT1 was markedly decreased specifically in the jejunal segment, which was supported by the decrease in PEPT1 expression on brush border membrane (BBM) of intestinal epithelial cells. Since no change in antipyrine permeability and significant increase in FITC dextran-4 permeability were observed in 5-HT-excessive rats, the enhanced permeability for CEX would be attributed to the opening of tight junction, which was supported by the significant decrease in transmucosal electrical resistance. In 5-HT-excessive rats, furthermore, total body clearance of CEX tended to be larger and the decrease in PEPT2 expression on BBM in kidneys was suggested to be one of the reasons for it.

Conclusions

5-HT-excessive condition enhanced the oral bioavailability of CEX in rats, which would be attributed to the enhanced permeability across the intestinal mucosa via passive diffusion through the paracellular route even though the transport via PEPT1 was decreased.

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Acknowledgements

This research was supported in part by the grant-in-aid for Scientific Research (C) from the Japan Society for the Promotion of Science (KH).

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Author notes

  1. Shun Nakashima

    Present address: Global CMC Regulatory Office, Regulatory Affairs Department, Otsuka Pharmaceutical Co. Ltd., 3-2-27 Otedori Chuo-ku, Osaka, 540-10021, Japan

  2. Takeharu Iwamoto

    Present address: Scientific Crime Laboratory, Kanagawa Prefectural Police Head Quarter, 155-1 Yamashita-cho, Naka-ku, Yokohama, Kanagawa, 231-0023, Japan

  3. Ken-ichi Ogawara

    Present address: Laboratory of Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita, Higashinada-ku, Kobe, Hyogo, 658-8558, Japan

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan

    Shun Nakashima, Takeharu Iwamoto, Masashi Takanashi, Ken-ichi Ogawara, Masato Maruyama & Kazutaka Higaki

  2. Central Hyogo Area, Hanshin Dispensing Pharmacy, I & H Co., Ltd., 1-18 Ohmasu-cho, Ashiya, Hyogo, 659-0066, Japan

    Masashi Takanashi

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Contributions

Shun Nakashima; Methodology, Writing, Acquisition, Analysis and interpretation of data: Takeharu Iwamoto; Acquisition, Analysis and interpretation of data: Masashi Takanashi; Acquisition of data: Ken-ichi Ogawara; Interpretation of data: Masato Maruyama; Interpretation of data: Kazutaka Higaki; Conceptualization, Methodology, Writing, Visualization, interpretation of data, Supervision.

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Correspondence to Kazutaka Higaki.

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Nakashima, S., Iwamoto, T., Takanashi, M. et al. Effect of Excessive Serotonin on Pharmacokinetics of Cephalexin after Oral Administration: Studies with Serotonin-Excessive Model Rats. Pharm Res 39, 2163–2178 (2022). https://doi.org/10.1007/s11095-022-03325-8

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