Nasal absorption and pharmacokinetic disposition of salmon calcitonin modified with low molecular weight polyethylene glycol.
This study was performed to examine the absorption potential of polyethylene glycol (PEG)-modified salmon calcitonin (sCT) in rats administered via the nasal route. Previous studies have used relatively high molecular weight polyethylene glycols (e.g., > or =5000 daltons) for PEG-modification of sCT to provide increased metabolic stability and biological half-life. Unlike these studies, the present study utilized a low molecular weight succinimidyl-propionated monomethoxy-poly(ethylene glycol) (MW 2000). It was hypothesized that the potential for membrane transport would not be significantly altered due to a relatively small increase in the molecular size while the metabolic stability would be enhanced due to resistance to proteolytic degradation. After PEG-modification of sCT, the mono-PEG positional isomer (mono-PEG2k-sCT) was separated from di-PEG2k-sCT, tri-PEG2k-sCT, and unmodified sCT by size exclusion chromatography. The mono-PEG2k-sCT and unmodified sCT were radioiodinated, and the resulting 125I-sCT and 125I-mono-PEG2k-sCT were separated from free iodine by RP HPLC and confirmed by MALDI-TOF MS. The 125I-sCT and 125I-mono-PEG2k-sCT were administered to rats via the nasal route, and serial blood, tissue, and urine samples were taken for up to 36 h for the determination of radioactivity. Mono-PEG2k-sCT exhibited significantly increased AUC (20,638 vs. 3,650 ng.min/ml), tmax (520 vs. 77 min), and t1/2,lambdaz (923 vs. 199 min) compared with unmodified sCT. This study demonstrates that mono-PEG2k-sCT is absorbed systemically when given by the intranasal route, exhibiting altered absorption kinetics compared with unmodified sCT.
College of Pharmacy, Sungkyunkwan University, Korea.
Beom Soo
BS
Shin
Ji Hoon
JH
Jung
Kang Choon
KC
Lee
Sun Dong
SD
Yoo
D000042:Absorption; D000818:Animals; D002116:Calcitonin / Q000737:chemistry / Q000493:pharmacokinetics*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D007457:Iodine Radioisotopes; D007536:Isomerism; D008970:Molecular Weight; D009297:Nasal Mucosa / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D007457:Iodine Radioisotopes; D011092:Polyethylene Glycols; C028815:salmon calcitonin; D002116:Calcitonin; D010447:Peptide Hydrolases