Pharmacokinetic-pharmacodynamic (PK-PD) modeling of cardiovascular effects of metoprolol in spontaneously hypertensive rats: a microdialysis study

Abstract

The present work addressed possible alterations in the pharmacokinetics and the in vivo pharmacodynamic of metoprolol (MET) in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals by means of the microdialysis technique. The correlation between MET unbound plasma concentrations and its pharmacological effects, such as heart rate and blood pressure change, was also examined in SH and WKY rats by the application of a PK-PD model. MET dialysate concentrations and its chronotropic and blood pressure effect were determined during 3 h after the administration of 3 and 10 mg.kg(-1) of the drug. A PK-PD model with a separate effect compartment was used to analyse the data. A good correlation between plasma MET concentrations and its hypotensive and chronotropic effect was found in all experimental groups. Although a greater maximal effect (E(max)) for the antihypertensive effect of MET was observed in SH rats (WKY: E(max): -17+/-1 mmHg; SH: E(max): -28+/-4 mmHg; P<0.05 versus WKY rats), no differences were found in the concentration yielding half-maximal response (IC(50)) comparing SH (IC(50): 583+/-146 ng x ml(-1)) and WKY animals (IC(50): 639+/-187 ng x ml(-1)). The bradycardic effect of MET was greater in SH rats (E(max): -29+/-1%, P<0.05 versus WKY rats) than in WK animals (E(max): -22+/-2%), but no differences were observed in the IC(50) comparing both experimental groups (WKY: IC(50): 187+/-53 ng x ml(-1); SH: IC(50): 216+/-62 ng x ml(-1)). Pharmacokinetic analysis shows that the volume of distribution of MET was greater in SH rats (Vd: 3.4+/-0.5 l, P<0.05 versus WKY rats) with regard to Wistar Kyoto (WKY) animals (Vd: 1.9+/-0.2 l). The results suggest that the pharmacokinetic behaviour of metoprolol are modified in SH rats, resulting in an increased volume of distribution. A greater maximal efficacy to the hypotensive effect of metoprolol was observed in SH rats, suggesting participation of beta-adrenoceptors in the maintenance of the hypertension. Also, a greater chronotropic response to metoprolol was found in the hypertensive group compared with WKY animals, suggesting that, at least in part, the greater cardiac effect of metoprolol explained the enhanced hypotensive response of the beta blocker in the SH animals.