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

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.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Di Verniero, Carla. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Opezzo, Javier A.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentin

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

The cardiovascular effects and mechanism of antihypertensive response of carvedilol were assessed in fructose fed rats using pharmacokinetic–pharmacodynamic (PK-PD) modelling. Male Sprague Dowley rats were randomly divided into two groups: control rats received water for 6 weeks while fructose rats received fructose solution (10 %w/v) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modelling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Fructose feeding increased volume of distribution of both enantiomers. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in fructose rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in fructose rats. Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups with increased distribution in fructose fed rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in fructose rats compared with control rats, which is not related to enhanced sympatholytic activity. Therefore, pleiotropic effects of carvedilol, such as antioxidant activity, seem to contribute to its enhanced antihypertensive activity in this experimental model of metabolic syndrome.Fil: Bertera, Facundo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Di Verniero, Carla Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Mayer, Marcos Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Chiappetta, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; ArgentinaFil: Buontempo, Fabián. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Polizio, Ariel Héctor. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentin