Absorption Enhancement of a Protein Drug by Nitric Oxide Donor: Effect on Nasal Absorption of Human Granulocyte Colony-Stimulating Factor

• Published in: Journal of drug targeting 2000, Vol.8 (3), p.185-194
• Main Authors: Watanabe, Yoshiteru, Utoguchi, Naoki, Ishii, Akiko, Tai, Yukiko, Shiota, Hiroyuki, Kurai, Hirono, Matsumoto, Mitsuo
• Format: Article
• Language: English
• Subjects: Absorption-enhancing effect of nitric oxide; Administration, Intranasal; Animals; Biological and medical sciences; Cells, Cultured; General pharmacology; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - blood; Granulocyte Colony-Stimulating Factor - pharmacokinetics; Humans; Leukocyte Count; Male; Medical sciences; Nasal administration; Nasal Mucosa - drug effects; Nasal Mucosa - metabolism; nitric oxide; Nitric oxide donor; Nitric Oxide Donors - administration & dosage; Nitric Oxide Donors - pharmacokinetics; Penicillamine - administration & dosage; Penicillamine - analogs & derivatives; Penicillamine - pharmacokinetics; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rabbits; Recombinant Proteins; S-nitroso-N-acetyl-DL-penicillamine; S-nitroso-N-acetyl-penicillamine
• ISSN: 1061-186X; 1029-2330
• DOI: 10.3109/10611860008996864

AbstractThe objective of this study was to evaluate the effect of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), on the nasal absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rabbits and to evaluate the irritation (cytotoxicity) potential of the NO donor on the mucosal membrane using a cultured cell system (strain KB, human epidermoid carcinoma of the floor of the mouth). Significantly higher serum G-CSF concentration and increased total leukocyte count in the peripheral blood were observed after coadministration of rhG-CSF (100 μg/kg) with SNAP at various doses (0.3-3.3 mg/kg). The serum G-CSF concentration and the increased total leukocyte count were markedly decreased by the presence of the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazole-l-oxyl 3-oxide sodium salt (carboxy-PTIO), in combination with rhG-CSF and SNAP. However, no significant inhibitory effect of glutathione (peroxynitrite scavenger) on the absorption-enhancing effect of SNAP was observed. These results suggest that carboxy-PTIO inhibits the absorption-enhancing effect of NO released from SNAP. We found that SNAP has a very low potential for cytotoxicity, as evaluated by the cell detachment assay, release of lactate dehydrogenase (LDH) from cultured cells and morphological observations of nasal tissue of rabbits. It is concluded that a NO donor such as SNAP is a promising absorption enhancer for nasal protein-drug delivery.