Reversible lipidization prolongs the pharmacological effect, plasma duration, and liver retention of octreotide.
OBJECTIVE
Octreotide (OCT) was reversibly lipidized to improve the pharmacological effect and to increase the plasma half-life and the liver retention of OCT for greater therapeutic potential in the treatment of liver cancers such as hepatocellular carcinoma.


METHODS
OCT was chemically modified using reversible aqueous lipidization (REAL) technology. REAL-modified OCT (REAL-OCT) was characterized with high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. A single dose of OCT or REAL-OCT or vehicle only was subcutaneously administered to male Sprague-Dawley rats, and the plasma growth hormone (GH) levels were measured after an intravenous injection of 2.5 microg/kg of growth hormone releasing factor (GRF) to assess the ability of REAL-OCT on GH inhibition. Radio-iodinated Tyr3-OCT (TOC) and REAL-TOC were used for pharmacokinetic studies.


RESULTS
At 0.1 mg/kg, REAL-OCT inhibited the GRF-induced GH surge in rats for a greater than 24-h period in comparison to the 6-h period for OCT. The distribution and elimination half-life for 125I-REAL-TOC were 1.4 h and 6.6 h, respectively, which were significantly longer than those of 125I-TOC. Sustained high blood concentrations and reduced in vivo degradation were observed for 125I-REAL-TOC. In addition, 125I-REAL-TOC appeared to be targeted to the liver with persistent high liver retention.


CONCLUSIONS
REAL-OCT has a significantly enhanced pharmacological effect, and this is most likely due to the favorable changes in the pharmacokinetic parameters upon lipidization. The observed liver targeting effect of REAL-TOC suggests that REAL-OCT might be advantageous over OCT in treating liver cancers.
Yuan
Liyun
L
Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90033, USA.
Wang
Jeff
J
Shen
Wei-Chiang
WC
D000818:Animals; D002626:Chemistry, Pharmaceutical; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D015282:Octreotide / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008055:Lipids; D013006:Growth Hormone; D015282:Octreotide