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Drug Metab Pharmacokinet. 2019 Apr;34(2):159-162. doi: 10.1016/j.dmpk.2019.01.001. Epub 2019 Jan 19.

Proteomic analysis of small intestinal epithelial cells in antibiotic-treated mice: Changes in drug transporters and metabolizing enzymes.

Author information

1
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima 771-0192, Japan. Electronic address: Kuno.Takuya@otsuka.jp.
2
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. Electronic address: hirayama.mio@gmail.com.
3
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan. Electronic address: ishingo@kumamoto-u.ac.jp.
4
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan. Electronic address: sohtsuki@kumamoto-u.ac.jp.

Abstract

Antibiotics act on bacterial flora originally present in the intestine, and changes in the intestinal flora have various effects on the host. This study investigated changes in the protein levels of drug transporters and metabolizing enzymes in the small intestines of antibiotic-treated mice by proteomic analysis. After the oral administration of non-absorbable antibiotics (vancomycin and polymyxin B) for 5 days, 15 drug transporter or metabolizing enzyme proteins had significantly changed levels among 1780 proteins identified in small intestinal epithelial cells. Of these, the levels of peptide transporter 1 (Pept1), multidrug resistance protein 1a (Mdr1a), and multidrug resistance-associated protein 2 (Mrp2) were increased approximately 2-fold. In addition, the levels of two Cyp4f proteins were decreased and those of Cyp4b1, Ces1d, and three glutathione S-transferase (Gst) proteins were increased. Our results indicate that the oral administration of antibiotics changes the levels of proteins related to the absorption and metabolism of drugs in the small intestine, and suggest that substrate drugs of these proteins have a risk for indirect drug interactions with antibacterial drugs via the intestinal flora.

KEYWORDS:

Antibiotics; Drug metabolizing enzyme; Drug transporter; Intestinal flora; Proteomics; Small intestine

PMID:
30826185
DOI:
10.1016/j.dmpk.2019.01.001

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