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This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.071290v1 312/1/248    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hiraoka, H. Articles by Higaki, K. Search for Related Content PubMed PubMed Citation Articles by Hiraoka, H. Articles by Higaki, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB QUINIDINE QUINIDINE SULFATE

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Up-Regulation of P-Glycoprotein Expression in Small Intestine under Chronic Serotonin-Depleted Conditions in Rats

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama, Japan

To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HT-depleted rats prepared by intraperitoneal administration of p-chlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum, and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush-border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under the 5-HT-depleted condition.

Address correspondence to: Dr. Kazutaka Higaki, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Okayama 700-8530, Japan. E-mail: higaki{at}pheasant.pharm.okayama-u.ac.jp

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