Estimation of bioavailability of salmon calcitonin from the hypocalcemic effect in rats (II): effect of protease inhibitor on the pharmacokinetic-pharmacodynamic relationship after intranasal administration.
Assessment of the extent of bioavailability (EBA) of salmon calcitonin (sCT) from hypocalcemic effects after intranasal administration was presented in rats. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model with the endogenous Ca regulation system was applied. The influence of camostat mesilate, a protease inhibitor, on absorption of sCT was also estimated. Camostat, coadministered intravascularly, delayed the elimination of sCT. Although the hypocalcemic effect of sCT after i.v. administration was accelerated when camostat was coadministered intravenously, the enhanced effect could not be expressed only by pharmacokinetic change of sCT, and then the pharmacological data in the presence of camostat were analyzed to obtain optimal PD parameters. For the absorption of sCT after i.n. administration, a saturable absorptive process and a zero-order kinetic clearance from the nasal cavity were introduced to the model. The regression curves fitted the observed data, and camostat caused both an increase in maximum absorption rate and a decrease in the clearance parameter compared with the control. According to this modified PK-PD relationship, plasma sCT concentrations following i.n. administration of sCT with camostat were predicted well using its pharmacological effects. The EBA of sCT calculated from the simulated concentrations increased more than 4-folds compared with the control study. These results indicate the potential for prediction of plasma sCT concentration from the hypocalcemic effect.
Miyazaki
Makoto
M
Department of Pharmaceutics, Osaka University of Pharmaceutical Sciences, Japan.
Nakade
Susumu
S
Iwanaga
Kazunori
K
Morimoto
Kazuhiro
K
Kakemi
Masao
M