title: Effect of pluronic F68 block copolymer on P-glycoprotein transport and CYP3A4 metabolism.
abstract: The aim of this work was to investigate the effects of pluronic F68 block copolymer on the P-gp-mediated transport of celiprolol (CEL) and CYP3A4-mediated formation of midazolam (MDZ) metabolite 1'-hydroxymidazolam. Over a range from 0.03 to 0.3%, pluronic F68 increased apical-to-basolateral permeability (AP-BL) and decreased basolateral-to-apical permeability (BL-AP) of the P-gp substrate CEL in Caco-2 cell monolayer with the efflux ratio values of 2.8+/-0.3 (0.03%), 2.6+/-0.3 (0.1%), 2.3+/-0.2 (0.3%), respectively. CEL transport across the intestinal mucosa in the everted gut sac model was also enhanced by the P-gp inhibitor verapamil and the pharmaceutical excipient pluronic F68. Furthermore, CYP3A4-catalyzed formation of 1'-hydroxymidazolam was inhibited by pluronic F68 with IC(50) and K(i) values of 0.11 and 0.16 mg/ml, respectively. The results indicate that pluronic F68 is a potent in vitro inhibitor of both P-gp and CYP3A4, suggesting a potential for pluronic F68 to modify the pharmacokinetics of orally administered drugs that are P-gp and/or CYP3A4 substrates in vivo.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Jiangeng
authors.initials: J
authors.lastname: Huang
authors.forename: Luqin
authors.initials: L
authors.lastname: Si
authors.forename: Lingli
authors.initials: L
authors.lastname: Jiang
authors.forename: Zhaoze
authors.initials: Z
authors.lastname: Fan
authors.forename: Jun
authors.initials: J
authors.lastname: Qiu
authors.forename: Gao
authors.initials: G
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D017272:Celiprolol / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008874:Midazolam / Q000031:analogs & derivatives / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D020442:Poloxamer / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D020442:Poloxamer; D017272:Celiprolol; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam