Effects of polyoxyethylene (40) stearate on the activity of P-glycoprotein and cytochrome P450.
The present study was aimed to investigate the effects of polyoxyethylene (40) stearate (PS), a non-ionic surfactant, on the activity of P-glycoprotein (P-gp) and six major cytochrome P450 (CYP) isoforms. An in vitro diffusion chamber system was utilized to estimate the effects of PS concentration on the transport characteristics of Rhodamine 123 (R123) and Rhodamine 110 (R110), a standard P-gp substrate and nonsubstrate, respectively, across the excised intestinal segments of rat. Caco-2 cells were cultured to investigate the mechanisms by estimating the effects of PS on intracellular ATP levels, P-gp ATPase activity and membrane fluidity. The obtained results showed that PS inhibited P-gp mediated efflux in a concentration-dependent manner mainly by modulating substrate-stimulated P-gp ATPase activity. On the other hand, human liver microsomes were utilized to examine the inhibitive potential of PS on six major CYP isoforms. Inhibitive potential on two of these CYP2C9 and CYP2C19 was found to be clinically significant. In conclusion, PS is potentially useful as a pharmaceutical ingredient to improve the oral bioavailability of coadministered P-gp substrates and substrates for certain CYP isoforms.
Zhu
Saijie
S
Department of Pharmaceutics, School of Pharmacy, Fudan University, Yixueyuan Road 138, Shanghai 200032, People's Republic of China.
Huang
Rongqin
R
Hong
Minghuang
M
Jiang
Yanyan
Y
Hu
Zhuohan
Z
Liu
Chen
C
Pei
Yuanying
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008823:Micelles; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D012235:Rhodamines / Q000493:pharmacokinetics; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D007527:Isoenzymes; D008823:Micelles; D012235:Rhodamines; C049025:rhodamine 110; C526284:polyoxyethylene 40 stearate; D020112:Rhodamine 123; D011092:Polyethylene Glycols; D003577:Cytochrome P-450 Enzyme System