Analysis of transient and reversible effects of poly- l-arginine on the in vivo nasal absorption of FITC-dextran in rats

• Published in: Journal of controlled release 2002-08, Vol.82 (2), p.263-275
• Main Authors: Ohtake, Kazuo, Natsume, Hideshi, Ueda, Hideo, Morimoto, Yasunori
• Format: Article
• Language: English
• Subjects: Absorption - drug effects; Absorption enhancer; Administration, Intranasal; Animals; Biodegradation, Environmental; Biological and medical sciences; Dextrans - blood; Dextrans - pharmacokinetics; Fluorescein-5-isothiocyanate - analogs & derivatives; Fluorescein-5-isothiocyanate - pharmacokinetics; General pharmacology; Male; Medical sciences; Microscopy, Electron, Scanning; Molecular Weight; Nasal drug delivery system; Nasal Mucosa - metabolism; Nasal Mucosa - ultrastructure; Paracellular permeability; Peptides - pharmacokinetics; Peptides - pharmacology; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly- l-arginine; Rats; Rats, Wistar; Reversible enhancement
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(02)00128-1

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.