Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in aN^G-nitro-l-arginine methyl ester rat model of secondary hypertension

Abstract

Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L-NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

“…Spectral analysis of blood pressure recording in rats has established that variability at the low frequency (LF) domain is affected by vascular sympathetic tone and endothelial-derived NO and the normalization of LF by high frequency (HF) variability (LF/HF ratio) represents a validated marker of sympathetic vascular activity in preclinical and clinical studies [57][58][59][60]. By using an inhibitory indirect physiological model, we have found a good relationship between racemic carvedilol plasma concentrations and their effect on the LF/HF ratio, suggesting that PK/PD modeling could be a powerful tool for the assessment of the effects of third-generation β-blockers on sympathetic vascular activity [31,32]. In a previous study, a greater sympatholytic activity of carvedilol was found in L-NAME treated rats than in control normotensive rats, evidenced by a lower concentration that produces 50% of vascular sympathetic tone inhibition (IC 50 ) in the hypertensive group [31].…”

“…PK/PD properties of carvedilol have been compared in L-NAME hypertensive rats and normotensive rats by means enantioselective PK-PD modeling [31]. While S-carvedilol plasma levels were correlated with the chronotropic response by using an effect compartmental model, total racemic concentrations of carvedilol were related with the blood pressure lowering response considering that the R-enantiomer shows α-blocking activity [31].…”

“…PK/PD properties of carvedilol have been compared in L-NAME hypertensive rats and normotensive rats by means enantioselective PK-PD modeling [31]. While S-carvedilol plasma levels were correlated with the chronotropic response by using an effect compartmental model, total racemic concentrations of carvedilol were related with the blood pressure lowering response considering that the R-enantiomer shows α-blocking activity [31]. Although the PK/PD parameters of the S-carvedilol chronotropic effect, including E max and EC 50 , were not altered in L-NAME rats when compared with normotensive animals, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition [31].…”

“…An alternative PK/ PD model designed by Schoemaker et al [28], which is based on the replacement of EC 50 by S 0 (initial sensitivity to the drug) in the E max equation, allows a better estimation of PK/PD parameters when maximal response cannot be attained. Nevertheless, experimental studies with β-blockers have shown the possibility to achieve m aximal response with large doses w ithout inducing toxic effects or excessive blood pressure reduction [30][31][32].…”

“…For instance, vascular sympathetic tone can be considered as a physiological parameter constantly that is produced through zero-order kinetics (K in ) and removed in firstorder kinetics with a rate constant K out ( Figure 2). In this case, third-generation β-blockers with α-blocking properties, such as carvedilol, are able to inhibit the production of the sympathetic tone (inhibition of K in ), thereby affecting its magnitude [31].…”