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

Abstract

The present work addressed possible alterations inthe pharmacokinetics and the in vivo pharmacodynamic ofmetoprolol (MET) in spontaneously hypertensive (SH) ratsand Wistar Kyoto (WKY) animals by means of the microdialysistechnique. The correlation between MET unboundplasma concentrations and its pharmacological effects, such asheart rate and blood pressure change,was also examined in SHand WKY rats by the application of a PK-PD model. METdialysate concentrations and its chronotropic and bloodpressure effect were determined during 3 h after theadministration of 3 and 10 mg.kg−1 of the drug. A PK-PDmodel with a separate effect compartment was used toanalyse the data. A good correlation between plasma METconcentrations and its hypotensive and chronotropic effectwas found in all experimental groups. Although a greatermaximal effect (Emax) for the antihypertensive effect of METwas observed in SH rats (WKY: Emax: −17±1 mmHg; SH:Emax: −28±4 mmHg; P<0.05 versus WKY rats), no differenceswere found in the concentration yielding half-maximalresponse (IC50) comparing SH (IC50: 583±146 ng.ml−1) andWKY animals (IC50: 639±187 ng.ml−1). The bradycardiceffect of MET was greater in SH rats (Emax: −29±1%, P<0.05versus WKY rats) than in WK animals (Emax: −22±2%), butno differences were observed in the IC50 comparing bothexperimental groups (WKY: IC50: 187±53 ng.ml−1; SH: IC50:216±62 ng.ml−1). Pharmacokinetic analysis shows that thevolume of distribution of MET was greater in SH rats (Vd:3.4±0.5 l, P<0.05 versus WKY rats) with regard to WistarKyoto (WKY) animals (Vd: 1.9±0.2 l). The results suggestthat the pharmacokinetic behaviour of metoprolol aremodified in SH rats, resulting in an increased volume ofdistribution. A greater maximal efficacy to the hypotensiveeffect of metoprolol was observed in SH rats, suggestingparticipation of â-adrenoceptors in the maintenance of thehypertension. Also, a greater chronotropic response tometoprolol was found in the hypertensive group comparedwith WKY animals, suggesting that, at least in part, thegreater cardiac effect of metoprolol explained the enhancedhypotensive response of the beta blocker in the SH animals.