Regional differences in bioavailability of an opioid tetrapeptide in vivo in rats after administration to the respiratory tract.
TArPP (Tyr-D-Arg-Phe-Phe-NH(2)), 1-10 micromol/kg, was administered to anesthetized rats by nasal microinfusion, intratracheal microinfusion, intratracheal nebulization, aerosol inhalation, and i.v. bolus and infusion. Plasma concentrations of TArPP and its deamidated metabolite were determined by LC-MS-MS. Regional differences in bioavailability (F), first-pass metabolism, and absorption rate were found for TArPP after delivery to the respiratory tract. Absorption was rapid after both pulmonary and nasal administration (t(max) approximately 10-20 min). After nasal microinfusion, F was 52 +/- 9%. For all the pulmonary groups, F was higher (72-114%). First-pass metabolism of TArPP was lower in the lung than in the nasal cavity. It is evident that the pulmonary route is attractive for successful systemic delivery of small, hydrophilic and enzymatic susceptible peptides.
Krondahl
Eva
E
Department of Pharmacy, Uppsala University, Box 580, BMC, SE-751 23, Uppsala, Sweden.
Tronde
Ann
A
Eirefelt
Stefan
S
Forsmo-Bruce
Heidi
H
Ekström
Gunilla
G
Bengtsson
Ursula Hultkvist
UH
Lennernäs
Hans
H
D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000336:Aerosols / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability; D004745:Enkephalins / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics*; D018847:Opioid Peptides / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism
D000336:Aerosols; D004745:Enkephalins; D009842:Oligopeptides; D018847:Opioid Peptides; C111156:tyrosyl-arginyl-phenylalanyl-phenylaninamide