Reversible lipidization for the oral delivery of leu-enkephalin.
The endogenous opioid peptide leu-enkephalin (ENK) was chemically modified by a method known as reversible aqueous lipidization (REAL) with a novel amine-reacting lipophilic dimethylmaleic anhydride analog, 3,4-bis(decylthiomethyl)-2,5-furandione. The binding affinity of the product, REAL-ENK, to opioid receptors was greatly reduced. This prodrug was stable in neutral and basic phosphate buffers but underwent rapid hydrolysis under acidic conditions in the presence of 50% acetonitrile. It also showed increased stability toward enzymatic degradations in various tissue preparations. The half-lives of REAL-ENK in mouse small intestinal mucosal homogenate and liver homogenate were 12 and 80 min, representing a 12- and 32-fold increase over those of ENK itself. In contrast to ENK (t(1/2) 6.7 min), REAL-ENK was stable in mouse plasma. More importantly, REAL-ENK produced significant and sustained antinociception mediated by peripheral opioid receptors in a rodent inflammatory pain model. Pharmacokinetic studies employing a radioimmunoassay (RIA) demonstrated that significantly higher and sustained plasma peptide levels were detected up to 24 h following the oral administration of REAL-ENK in normal mice. The peak concentration and area under the curve of oral REAL-ENK were 4.4 and 21 times higher than that of oral ENK. Our results indicate that like its disulfide-based counterpart, amine-based REAL may be an enabling technology which can be applied to enhance metabolic stability, increase oral absorption, and preserve and possibly prolong the pharmacological activity of peptide drugs.
Wang
Jeffrey
J
College of Pharmacy, Western University of Health Sciences, Department of Pharmaceutical Sciences, Pomona, CA 91766, USA. jwangwesternu.edu
Hogenkamp
Derk J
DJ
Tran
Minhtam
M
Li
Wen-Yen
WY
Yoshimura
Ryan F
RF
Johnstone
Timothy B C
TB
Shen
Wei-Chiang
WC
Gee
Kelvin W
KW
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D004743:Enkephalin, Leucine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D051379:Mice; D011863:Radioimmunoassay; D014018:Tissue Distribution
D008055:Lipids; D004743:Enkephalin, Leucine