Oral Delivery of Mono-PEGylated sCT (Lys18) in Rats: Regional Difference in Stability and Hypocalcemic Effect

Abstract

In the in vitro experiment using a luminal, mucosal, and fecal fluid/extract from jejunum and colon of a rat, Lys18-residue modified mono-PEG2k-sCT (Lys18-PEG2K-sCT) exhibited a longer half-life than salmon calcitonin (sCT) in a colonic fluid and its extract. A physical adsorption study showed that Lys18-PEG2K-sCT had lower adsorption in the feces than sCT over an 8-hr period. An absorption study of the sCT and Lys18-PEG2K-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-PEG2K-sCT (5 µg/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 (% maxd) 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-PEG2K-sCT. The relative pharmacological bioavailability of the intracolonically administered Lys18-PEG2K-sCT was 2.1-fold higher than sCT and the absolute pharmacological bioavailability was 73.59% of IV-injected sCT in an 8-hr period. Overall, this study highlights the feasibility of the oral delivery of Lys18-PEG2K-sCT in achieving a sustained calcium-lowering effect.