Regional oral absorption, hepatic first-pass effect, and non-linear disposition of salmon calcitonin in beagle dogs

Abstract

The dose-dependent disposition, first pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100–1000 μg) demonstrated higher total plasma clearance (CL) and V dss than the low dose groups (1–25 μg). However, the MRT did not change for doses ranging from 10 to 1000 μg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic first-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V dss values, and it is hypothesized that increased renal blood flow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.