Modulation of intestinal P-glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes

✍ Scribed by Yasushi Shono; Hisayo Nishihara; Yasuyuki Matsuda; Shiori Furukawa; Naoki Okada; Takuya Fujita; Akira Yamamoto

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 123 KB
• Volume: 93
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20017

✦ Synopsis

Effects of various surfactants on the transport of rhodamine123, a P-glycoprotein (P-gp) substrate, across the isolated rat intestinal membranes were examined by an in vitro diffusion chamber system. The jejunal serosal-to-mucosal transport (Jsm) of rhodamine123 was more than threefold greater than its mucosal-toserosal transport (Jms), suggesting that the net movement of rhodamine123 across the rat jejunum was preferentially secretory direction. There exists a regional difference in the intestinal transport of rhodamine123 and the secretory directed transport was remarkably observed in the jejunum. The Jsm/Jms ratio of rhodamine123 decreased in the presence of 0.3 mM verapamil and 10 mM sodium azide (NaN 3 ) þ 1 mM sodium fluoride (NaF), confirming that rhodamine123 might be secreted from the intestinal tissue into the lumen by a P-gp-mediated efflux system. Nonionic surfactants [0.1% Cremophor EL, Tween 80 and n-dodecyl-b-D-maltopyranoside (LM)] reduced the Jsm/ Jms ratio of rhodamine123, whereas its ratio was not influenced in the presence of 0.1% cationic surfactant (hexadecyltrimethylammonium bromide, C 16 TAB) and anionic surfactant (sodium dodecyl sulfate, SDS). Therefore, these findings suggested that charge of surfactants was possibly related to the action of these surfactants on the intestinal absorption of P-gp substrates. On the other hand, the transfer of rhodamine123 was not affected by the addition of Cremophor EL to the serosal side. Because the c.m.c. of Cremophor EL is 0.0095 w/v%, interactions between rhodamine123 and the micellar form of Cremophor EL may decrease the P-gp-mediated efflux of rhodamine123 at higher concentrations. In the kinetic analysis, the V max value (nmol/min/g wet tissue) of rhodamine123 decreased, although the K m value (mM) was constant in the presence of Cremophor EL. Therefore, Cremophor EL inhibited the efflux transport of rhodamine123 in a noncompetitive manner. Cremophor EL did not affect the transport of [ 14 C]Gly-Sar and [ 3 H]3-O-methyl-D-glucose, suggesting that the action of Cremophor EL might be P-gp specific. These findings indicated that nonionic surfactants including Cremophor EL and Tween 80 may be useful pharmaceutical excipients for inhibiting the function of P-gp, thereby increasing the intestinal absorption of various drugs, which are secreted by a P-gp-mediated efflux system in the intestine.