title: Chitosan Influences the Expression of P-gp and Metabolism of Norfloxacin in Grass Carp.
abstract: The aim of this study was to investigate the relationship between the administration of chitosan (CTS), expression of permeability glycoprotein (P-gp), and the metabolism of norfloxacin (NOR) in Grass Carp Ctenopharyngodon idella. Fish were administrated with a single dose of either NOR, CTS, 1:5 NOR-CTS or 1:10 NOR-CTS. The P-gp expression was analyzed by immunohistochemistry and real time-PCR. The concentration of NOR was determined using HPLC. The mRNA and protein expression of P-gp in the fish intestine was significantly enhanced following a single dosage of 40 mg/kg NOR, and peak expression occurred at 3 h after drug administration (P < 0.05). A single dosage of both 1:5 NOR-CTS and 1:10 NOR-CTS reduced the intestinal P-gp expression to levels significantly lower than that from NOR alone (P < 0.05), but significantly higher than that from the control (P < 0.05). Interestingly, CTS alone also led to a slight decrease in P-gp expression. In addition, pharmacokinetic assays revealed a marked increase in area under the curve (AUC) of NOR with 1:5 and 1:10 NOR-CTS, by approximately 1.5-fold and threefold, respectively. Finally, the relative bioavailability of NOR after a single oral dosage of 1:5 and 1:10 NOR-CTS was enhanced to 148.02% and 304.98%, respectively. In this study, we demonstrated that the transmembrane glycoprotein P-gp regulates NOR metabolism in the intestine of Grass Carp, suggesting that NOR may be a direct substrate of P-gp. More importantly, we showed that CTS can inhibit P-gp expression in a dose-dependent manner and improve the relative bioavailability of NOR in this species.
authors.affiliation: a National Pathogen Collection Center for Aquatic Animals , Shanghai Ocean University , 999 Hucheng Huan Road, Shanghai , 201306 , China.
authors.forename: Kun
authors.initials: K
authors.lastname: Hu
authors.forename: Xinyan
authors.initials: X
authors.lastname: Xie
authors.forename: Yi-Ni
authors.initials: YN
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Jiming
authors.initials: J
authors.lastname: Ruan
authors.forename: Hao-Ran
authors.initials: HR
authors.lastname: Li
authors.forename: Tianyi
authors.initials: T
authors.lastname: Jin
authors.forename: Xian-Le
authors.initials: XL
authors.lastname: Yang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002347:Carps / Q000378:metabolism*; D048271:Chitosan / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D009643:Norfloxacin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D012333:RNA, Messenger; D048271:Chitosan; D009643:Norfloxacin