title: Enhanced brain delivery of the opioid peptide DAMGO in glutathione pegylated liposomes: a microdialysis study.
abstract: Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations. Microdialysis made it possible to determine free DAMGO in brain and plasma, while the GSH-PEG liposomal encapsulated DAMGO was measured with regular plasma sampling. The antinociceptive effect of DAMGO was determined with the tail-flick method. All samples were analyzed using liquid chromatography-tandem mass spectrometry. The short infusion of DAMGO resulted in a fast decline of the peptide concentration in plasma with a half-life of 9.2 ± 2.1 min. Encapsulation in GSH-PEG liposomes prolonged the half-life to 6.9 ± 2.3 h. Free DAMGO entered the brain to a limited extent with a steady state ratio between unbound drug concentrations in brain interstitial fluid and in blood (Kp,uu) of 0.09 ± 0.04. GSH-PEG liposomes significantly increased the brain exposure of DAMGO to a Kp,uu of 0.21 ± 0.17 (p < 0.05). By monitoring the released, active substance in both blood and brain interstitial fluid over time, we were able to demonstrate that GSH-PEG liposomes offer a promising platform for enhancing and prolonging the delivery of drugs to the brain.
authors.affiliation: Department of Pharmaceutical Biosciences, Box 591, SE-751 24 Uppsala, Sweden. annika.lindqvist@farmbio.uu.se
authors.forename: Annika
authors.initials: A
authors.lastname: Lindqvist
authors.forename: Jaap
authors.initials: J
authors.lastname: Rip
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Gaillard
authors.forename: Sven
authors.initials: S
authors.lastname: Björkman
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005978:Glutathione / Q000008:administration & dosage; D006207:Half-Life; D007262:Infusions, Intravenous; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D017551:Microdialysis; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D008081:Liposomes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D011092:Polyethylene Glycols; D005978:Glutathione