The disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg-1 of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg-1 of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two-fold greater and the corresponding elimination half-life (t 1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of 14C-salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the larger Vd observed in this group of rats. After the administration of 173 mg kg-1 of SA, no differences in CL, Vd, kk or t 1/2 were noted between the analbuminemic and control rats. Dose-dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA protein binding.

Animals↗

PubMedDate not supplied

Pharmacokinetic-pharmacodynamic modelling of DP-1904, a novel thromboxane synthetase inhibitor in rabbits, based on an indirect response model.

A new imidazole derivative, DP-1904, produces a selective, potent and long-acting inhibition of thromboxane A2 (TXA2) syntheses and platelet aggregation. This study was designed to investigate the pharmacokinetics and pharmacodynamics (PK/PD) of DP-1904. DP-1904 disappeared from plasma with a half-life of 20 min after i.v. dosing, and the bioavailability after oral dosing was approximately 70%. The level of serum TXB2, which is a pharmacological marker for thromboxane synthetase inhibition, was measured to characterize the pharmacodynamics of DP-1904. A marked reduction of serum TXB2 was exhibited within 1 h after both i.v. and oral doses, reflecting the rapid onset of action of DP-1904. Serum TXB2 returned to the basal level much more slowly after oral dosing than after i.v. dosing, due to the longer half-life after oral dosing. An Emax model was employed to fit the pharmacological data after oral dosing, and IC50 and Emax values were estimated to be 5.0 ng/ml and 81%, respectively. In order to test its predictability, the PK/PD model was then used to predict a pharmacological profile after i.v. dosing; good agreement between the observed and predicted values was achieved. Thus, the present modelling procedure may be useful for optimizing the therapeutic regimens of DP-1904.

Administration, Oral↗