Estimation of bioavailability of salmon calcitonin from the hypocalcemic effect in rats (I): pharmacokinetic-pharmacodynamic modeling based on the endogenous Ca regulatory system.

The hypocalcemic effect of salmon calcitonin (sCT) after intravenous administration was explained on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model with the endogenous Ca regulatory system in the rat. The pharmacokinetics of sCT described by a conventional two-compartment model showed the extremely rapid elimination of sCT from plasma (MRT; 6.86 min). The hypocalcemic effect of sCT reached a peak from 0.5 to 1.5 hrs after administration, and the peak time tended to prolong with increasing doses. This delay in pharmacological effect of sCT against plasma concentration may be a result of a summation of multiple actions of the endogenous Ca regulatory system including feedback control. The plasma Ca regulation system in the rat was investigated by i.v. bolus administration of calcium gluconate and/or endogenous (rat) calcitonin (rCT). Since non-linearity in the relationship between Ca and rCT concentrations in plasma was observed, we assumed that rCT was secreted in accordance with the plasma Ca level via an exponential function. The pharmacokinetics of rCT was represented as a linear one-compartment model. To link the rCT level with plasma Ca level, an additional effect compartment was required to explain the delay in onset and decline of the pharmacological effect. This Ca regulation model explained the observed Ca and rCT profiles in plasma after administration of Ca and/or rCT. The plasma Ca levels after administration of sCT could be well described by the present integrated model. This suggested the potential for prediction of plasma sCT concentration only from the hypocalcemic effect after extravascular administration of sCT, using this PK-PD model.

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.

Contribution of sympathetic nervous system activity during administration of carvedilol in rats with dilated cardiomyopathy.

We investigated the contribution of the sympathetic nervous system (SNS) in maintaining blood pressure during administration of carvedilol in rats with dilated cardiomyopathy, and examined whether SNS hyperactivity induced by high-dose carvedilol is related to severity of heart failure. The hypotensive effect of carvedilol in rats with heart failure (Group F) was not significantly different to that in rats without (Group N). However, enhancement of the plasma norepinephrine concentration during carvedilol administration in Group F was higher than in Group N. The constitutive plasma NE concentration in Group F (562 +/- 146 pg/ml) was significantly higher than in Group N (203 +/- 55 pg/ml) and there was a significant positive correlation between the heart weight to body weight ratio and the plasma norepinephrine concentration. Values for the maximal effect of the norepinephrine hypertensive effect during norepinephrine intravenous infusion (Emax) decreased, and plasma norepinephrine concentrations at half-maximal effect of the norepinephrine hypertensive effect (EC50) increased in Group F compared with Group N (20.8 +/- 6.1 and 28.6 +/- 2.2 mmHg, and 4.5 +/- 1.9 and 1.5 +/- 0.2 ng/ml, respectively). These results suggested that the number of receptors (Emax) and sensitivity (EC50) to the norepinephrine hypertensive effect decreased in Group F. Changes in these parameters in Group F corresponded with the results of a beta-adrenergic receptor binding assay using I-125 iodocyanopindolol (Bmax = 32 +/- 4 in Group F and 53 +/- 2 fmol/mg protein in Group N). These results showed that the SNS (presynaptic) activity increased and the SNS receptor sensitivity in the blood pressure regulation system decreased in heart failure. Therefore, high-dose carvedilol treatment should be used with caution to avoid worsening heart failure.

Hemodynamic effects of carvedilol infusion and the contribution of the sympathetic nervous system in rats with heart failure.

We investigated the contribution of the sympathetic nervous system (SNS) in maintaining the blood pressure and in regulating the cardiac function during and after carvedilol administration in rats with heart failure (group F). Left ventricular end-diastolic pressure, percent functional shortening, and rates of intraventricular pressure rise were significantly changed by carvedilol infusion as compared with the basal values in group N (normal rats), but not in group F. The left ventricular end-diastolic pressure was elevated, corresponding to the enhancement of the plasma norepinephrine (NE) concentration caused by carvedilol infusion, in group N. The enhancement of the plasma NE concentration induced by carvedilol administration in group F was higher than that in group N. The value for the maximal hypertensive effect of NE intravenous infusion (Emax) was decreased, and the plasma NE concentration at half-maximal effect (EC50) was increased in group F as compared with the values in group N. These results indicate that the SNS (presynaptic) activity is increased and that the SNS receptor sensitivity in the cardiovascular regulation system is decreased in heart failure.