Biol. Pharm. Bull., 30(7),1301-1307, July 2007

Regular Articles

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Yulian LIN,^a,b Qi SHEN,^c Hidemasa KATSUMI,^a Naoki OKADA,^d Takuya FUJITA,^e Xuehua JIANG,^b and Akira YAMAMOTO^*,a

^a Department of Biopharmaceutics, Kyoto Pharmaceutical University; Misasagi, Yamashina-ku, Kyoto 607-8414, Japan: ^b Department of Clinical Pharmacy, Pharmacy School of Sichuan University; Chengdu, Sichuan 610041, China: ^c School of Pharmacy, Shanghai Jiao Tong University; Dongcuan Road, 800, Shanghai 200240, China: ^d Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University; 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan: and ^e Ritsumeikan University College of Information Science and Engeneering; Kusatsu, Shiga 525-8577, Japan. * To whom correspondence should be addressed. e-mail: yamamoto@mb.kyoto-phu.ac.jp

Effects of Labrasol and other pharmaceutical excipients on the intestinal transport and absorption of rhodamine123, a P-glycoprotein substrate (P-gp) were examined. Intestinal transport and absorption studies were examined by an in vitro diffusion chamber method and an in situ closed loop method. We evaluated the intestinal membrane damage produced by Labrasol by measuring the release of protein and alkaline phosphatase (ALP). Labrasol (0.075-0.1% (v/v)) increased the absorptive transport of rhodamine123 and decreased its secretory transport in the in vitro transport studies. However, Labrasol did not change the transport of Lucifer yellow, a non-P-gp substrate, suggesting that the effect of Labrasol on the transport of drugs was specific for rhodamine123. We observed almost no intestinal membrane damage in the presence of Labrasol. These findings suggest that the increase in the absorptive transport of rhodamine123 in the presence of Labrasol may not be due to its intestinal membrane damage. In the in situ absorption studies, we found that Labrasol (0.1% (v/v)) significantly enhanced the intestinal absorption of rhodamine123 in rats, although the absorption enhancing effect of Labrasol was much less than that of verapamil. These findings suggest that low concentrations of Labrasol might inhibit the function of P-gp in the intestine, thereby increasing intestinal absorption and bioavailability of P-gp substrates including rhodamine123. However, we may also consider the contribution to the enhanced intestinal absorption of rhodamine123 via a passive transport in addition to the inhibitory action of Labrasol for the function of P-gp in the intestine.

Key words intestinal absorption; rhodamine123; P-glycoprotein; Labrasol; pharmaceutical excipient