title: P-glycoprotein efflux inhibition by amphiphilic diblock copolymers: relationship between copolymer concentration and substrate hydrophobicity.
abstract: The utilization of surfactants to increase intestinal absorption of drugs is a viable strategy that benefits from increases in drug solubilization and the potential for inhibition of P-glycoprotein (P-gp) mediated efflux. However, the effective concentration range for P-gp inhibition of most surfactants is defined over a narrow concentration range, below the critical micelle concentration (CMC), as a result of significant micelle sequestration of drug. Therefore, the objectives of these studies were to assess if association of P-gp substrates differing in hydrophobicity will impact the effective concentration range for P-gp inhibition by amphiphilic diblock copolymers based on methoxypolyethylene glycol-block-polycaprolatone (MePEG-b-PCL). Comparisons between the micelle association and Caco-2 cellular accumulation were evaluated using two structurally homologous P-gp substrates, the relatively hydrophobic R-6G and the hydrophilic R-123, over concentrations above and below the CMC for MePEG-b-PCL diblock copolymers. An approximately 3.75-fold enhancement of R-123 accumulation occurred with 2 mM MePEG17-b-PCL5, compared to approximately 1.25-fold for R-6G. This decrease in the accumulation enhancement corresponds with the higher R-6G fraction (0.75) associated at 2 mM MePEG17-b-PCL5 compared with R-123 (0.25). Interestingly, R-6G accumulation was enhanced over a very broad range of MePEG17-b-PCL5 concentrations below the CMC. This was in contrast to R-123, which demonstrated no enhancement below the CMC. A similar concentration dependent accumulation profile was seen with other surfactants such as vitamin E TPGS and Cremophor EL and with two other P-gp substrates differing in hydrophobicity, the relatively hydrophobic paclitaxel and hydrophilic doxorubicin. In conclusion, the effective concentration range for surfactant mediated inhibition of P-gp appears to depend on the P-gp substrate hydrophobicity.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy Building, Athens, Georgia 30602, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Zastre
authors.forename: John K
authors.initials: JK
authors.lastname: Jackson
authors.forename: Wesley
authors.initials: W
authors.lastname: Wong
authors.forename: Helen M
authors.initials: HM
authors.lastname: Burt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D018938:Caco-2 Cells; D004317:Doxorubicin / Q000737:chemistry; D005027:Ethylene Oxide / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry; D011092:Polyethylene Glycols; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007783:Lactones; C400421:PLC(20)-b-PEO(44); D013501:Surface-Active Agents; D011092:Polyethylene Glycols; D004317:Doxorubicin; C028210:monomethoxypolyethylene glycol; D005027:Ethylene Oxide; D017239:Paclitaxel