title: Effect of pluronic P123 and F127 block copolymer on P-glycoprotein transport and CYP3A metabolism.
abstract: The aim of the present study was to evaluate the effect of pluronic P123 (P123) and pluronic F127 (F127) on intestinal P-glycoprotein (P-gp) and cytochrome P450 3A using the specific substrates rhodamine-123 (R-123) and midazolam, respectively. Caco-2 cells and everted gut sacs were used as models of intestinal mucosa to assess intestinal absorption of R-123, while rat intestinal microsomes were utilized to examine the effect of P123 and F127 on in vitro midazolam metabolism. P123 and F127 were observed to increase the intracellular accumulation of R-123 in Caco-2 cells in a dose-dependent manner. P123 significantly lowered the efflux ratio of R-123 at two concentrations in Caco-2 monolayers, whereas F127 lowered the efflux ratio only at 1%. Moreover, both pluronics markedly enhanced mucosal to serosal absorption of R-123 in excised ileum of rats. However, no significant difference in relative enzyme activity were observed between P123- or F127-treated and control groups, regardless of the concentrations of P123 and F127 studied. Collectively, these results obtained from the present study demonstrated that P123 and F127 were capable of inhibiting the intestinal P-gp activity, but had little or no effect on intestinal cytochrome P450 3A activity, indicating that P123 and F127 can potentially be used as pharmaceutical ingredients to improve the oral bioavailability of coadministered P-gp substrates via P-gp efflux pump inhibition.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Guan
authors.forename: Jiangeng
authors.initials: J
authors.lastname: Huang
authors.forename: Lan
authors.initials: L
authors.lastname: Zuo
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Xu
authors.forename: Luqin
authors.initials: L
authors.lastname: Si
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 / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D011060:Poloxalene / Q000494:pharmacology* / Q000633:toxicity; D020442:Poloxamer / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D020112:Rhodamine 123; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D020442:Poloxamer; D020112:Rhodamine 123; C464484:pluronic block copolymer P123; D011060:Poloxalene; D051544:Cytochrome P-450 CYP3A; C022616:thiazolyl blue; D008874:Midazolam