Analysis of transient and reversible effects of poly-L-arginine on the in vivo nasal absorption of FITC-dextran in rats.
We have investigated whether poly-L-arginine, with a mean molecular weights of 8.9 and 45.5 kDa (poly-L-Arg (10) and poly-L-Arg (50)), can induce transient and reversible effects involving enhancement of the nasal absorption of fluorescein isothiocyanate-labeled dextran (MW 4.4 kDa, FD-4) and determined the main pathway for the increased transport of FD-4 in rats in vivo. Pre-administration and repeated administration studies were conducted involving the selection of different time intervals between intranasal administration of poly-L-Arg and administration of FD-4, with and without poly-L-Arg, to characterize these transient and reversible effects. The degradation of poly-L-Args in a diluted nasal drip was determined from the fluorescence of degraded poly-L-Arg-fluorescamine products. In the pre-administration study, poly-L-Arg exhibited a transient effect on the increased nasal FD-4 absorption depending on its molecular weight, associated with the degradation rate of poly-L-Arg in mucus. In the repeated administration study, additional poly-L-Arg produced similarly enhanced FD-4 absorption. Confocal laser scanning microscopy showed that fluorescence of FD-4 after co-administration of poly-L-Arg (50) was confined mainly to the paracellular spaces. In conclusion, poly-L-Arg exhibited molecular weight-dependent transient and reversible effects on the enhancement of nasal FD-4 absorption paracellularly in rats in vivo. The enzymatic degradation of poly-L-Arg is one of the key determinants of the transient effect on in vivo enhanced absorption of FD-4.
Ohtake
Kazuo
K
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama, 350-0295, Japan.
Natsume
Hideshi
H
Ueda
Hideo
H
Morimoto
Yasunori
Y
D000042:Absorption / Q000187:drug effects; D000281:Administration, Intranasal; D000818:Animals; D001673:Biodegradation, Environmental; D003911:Dextrans / Q000097:blood / Q000493:pharmacokinetics*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D008855:Microscopy, Electron, Scanning; D008970:Molecular Weight; D009297:Nasal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D003911:Dextrans; D010455:Peptides; C015219:fluorescein isothiocyanate dextran; C015462:polyarginine; D016650:Fluorescein-5-isothiocyanate