Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats.
The present study examined the effects of lipid vehicle and intestinally based efflux processes on intestinal lymphatic transport of paclitaxel (PTX) in the mesenteric lymph duct-cannulated anesthetized rat model. PTX solution alone, PTX solution pretreated with the P-glycoprotein (P-gp) inhibitor verapamil and/or PTX and a 2:1 (w/w) mixture of linoleic acid:glycerol monooleate were administered intraduodenally to anesthetized rats. Coadministration of a mixture of linoleic acid-monoolein significantly increased the extent of intestinal lymphatic transport of PTX, but it had little impact on the absolute oral bioavailability of PTX. In contrast, pretreatment with verapamil increased both the extent of lymphatic transport (3.5-fold) and absolute oral bioavailability (1.8-fold). Further increase in the lymphatic transport (6.5-fold) and absolute oral bioavailability (1.8-fold) was achieved by the combination of pretreatment with verapamil and coadministration with the linoleic acid-monoolein mixture. These data indicate that the application of lipid vehicle holds promise for selectively targeted lymphatic delivery of PTX. P-gp inhibition can result in both increased intestinal lymphatic levels and absolute oral bioavailability of PTX.
a Department of Pharmacy, Huashan Hospital , Fudan University , Shanghai , P.R. China and.
Qingqing
Q
Cai
b Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education , Fudan University , Shanghai , P.R. China.
Xinxian
X
Deng
a Department of Pharmacy, Huashan Hospital , Fudan University , Shanghai , P.R. China and.
Zhongdong
Z
Li
b Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education , Fudan University , Shanghai , P.R. China.
Dianyun
D
An
b Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education , Fudan University , Shanghai , P.R. China.
Teng
T
Shen
a Department of Pharmacy, Huashan Hospital , Fudan University , Shanghai , P.R. China and.
Mingkang
M
Zhong
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002404:Catheterization; D005079:Excipients; D007413:Intestinal Mucosa / Q000378:metabolism; D019787:Linoleic Acid / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008643:Mesentery / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D005079:Excipients; D008055:Lipids; D019787:Linoleic Acid; D014700:Verapamil; D017239:Paclitaxel
Bioavailability; P-glycoprotein; cancer chemotherapy; intestinal absorption; lymphatic transport; paclitaxel; pharmacokinetics