Plasma-mediated release of morphine from synthesized prodrugs.
Two morphine prodrugs ('PDA' and 'PDB') were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5-10min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse>rat>guinea pig>human). Morphine's release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK-NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios.
Thomas
Thommey P
TP
Michigan Nanotechnology Institute for Medicine and Biological Sciences, Department of Internal Medicine, Division of Allergy, University of Michigan, 9220 MSRB III, Box 0648, Ann Arbor, MI 48109, USA.
Huang
Baohua
B
Desai
Ankur
A
Zong
Hong
H
Cheng
Xue-Min
XM
Kotlyar
Alina
A
Leroueil
Pascale R
PR
Dunham
Thomas
T
van der Spek
Abraham
A
Ward
Brent B
BB
Baker
James R
JR
D000701:Analgesics, Opioid / Q000097:blood* / Q000493:pharmacokinetics*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009020:Morphine / Q000097:blood* / Q000493:pharmacokinetics*; D009474:Neurons / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012015:Reference Standards
D000701:Analgesics, Opioid; D007202:Indicators and Reagents; D011355:Prodrugs; D017450:Receptors, Opioid, mu; D009020:Morphine; D002265:Carboxylic Ester Hydrolases