Oral delivery of mono-PEGylated sCT (Lys18) in rats: regional difference in stability and hypocalcemic effect.
In the in vitro experiment using a luminal, mucosal, and fecal fluid/extract from jejunum and colon of a rat, Lys18-residue modified mono-PEG(2k)-sCT (Lys18-PEG(2K)-sCT) exhibited a longer half-life than salmon calcitonin (sCT) in a colonic fluid and its extract. A physical adsorption study showed that Lys18-PEG(2K)-sCT had lower adsorption in the feces than sCT over an 8-hr period. An absorption study of the sCT and Lys18-PEG(2K)-sCT from the jejunum and colon using an in situ closed-loop technique in anesthetized rats showed a dose-dependent reduction in the plasma Ca2+ level but to a certain limit. Furthermore, the hypocalcemic response by intracolonic administration was significantly higher than the intrajejunal one, demonstrating that the colon had better absorption. In particular, Lys18-PEG(2K)-sCT (5 microg/rats) produced the most pronounced hypocalcemia after the intracolonic administration, which resulted in a sustained reduction in the serum calcium level over an 8-hr period, with a maximum reduction (% max(d)) of 38% after 4 hr. The overall reduction in the serum calcium levels, which was expressed as the net change in the AUC relative to the control over an 8-hr period, was 25.51 +/- 3.38 for Lys18-PEG(2K)-sCT. The relative pharmacological bioavailability of the intracolonically administered Lys18-PEG(2K)-sCT was 2.1-fold higher than sCT and the absolute pharmacological bioavailability was 73.59% of i.v.-injected sCT in an 8-hr period. Overall, this study highlights the feasibility of the oral delivery of Lys18-PEG(2K)-sCT in achieving a sustained calcium-lowering effect.
Mansoor
Saffar
S
Drug Targeting Laboratory, College of Pharmacy, SungKyunKwan University, Suwon City, Korea.
Youn
Yu Seok
YS
Lee
Kang Choon
KC
D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D002116:Calcitonin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003106:Colon / Q000378:metabolism; D004355:Drug Stability; D006996:Hypocalcemia / Q000139:chemically induced*; D007408:Intestinal Absorption; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011092:Polyethylene Glycols; C028815:salmon calcitonin; D002116:Calcitonin