EVALUATION OF THE CARDIOVASCULAR EFFECTS AND PHARMACOKINETICS OF THE COENCAPSULA- TION OF CARVEDILOL AND QUERCETIN IN NANOMICELLAR DISPERSIONS IN AN EXPERIMENTAL HYPERTENSION MODEL

ANA SOL RIESCO; JORGE ANDRÉS NARVÁEZ PARDO; AGUSTINA FREIRE; FLORENCIA CAPACCIOLI; MIGUEL ALLO; PEDRO FUENTES; MARCELA MORETTON; FERNANDO DOMINICI; PABLO EVELSON; ANDREA CARRANZA; CHRISTIAN HÖCHT

Congreso; LXVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2023

Carvedilol is a β-blocker used for the management of arterial hypertension, that is conditioned by its rapid systemic elimination. In previous studies, we showed that encapsulation of carvedilol in nanomicellar dispersions improved oral bioavailabilityand extended half-life of elimination. This technique also allows the co-encapsulation with lipophilic agents. Quercetin is a flavonoid with a potential antihypertensive effect since reduces inflammation and oxidative stress. Based on this evidence, the combination of carve-dilol and quercetin would represent a potential strategy to improve target organ damage protection. Aim: To evaluate the pharmacokinetic and hemodynamic response, as well as the impact on target-organ damage, of the oral administration of carvedilol, carvedilol/quercetin, and quercetin in spontaneously hypertensive rats (SHR).Methodology: Soluplus nano micellar dispersions were prepared with 3mg/ml carvedilol, 2mg/ml quercetin, and 3/2mg/ml carvedilol/quercetin. The pharmacokinetic profile, hemodynamic effects, and cardiac/vascular damage markers were evaluated in SHR after acute (single dose) and chronic treatment (8 weeks). Results: Sin-gle-dose carvedilol/quercetin showed a statistically greater area under the curve of carvedilol plasma levels compared to carvedilol(1461±210ng/ml.h vs 916±142ng/ml.h), and a greater reduction in heart rate (-23.2±2.8 vs -10.7±1.1%). After 8 weeks, carvedilol/quercetin induced a similar antihypertensive response compared with carvedilol (-12.7±0.7% vs -13.2±1.1%). However, the combination showed more protection against target organ damage than carvedilol, with a statistically significant decrease in cardiomyocyte size(902±51 vs. 610±30μm2) and the left ventricular fibrosis (5.98±0.5vs. 3.72±0.3μm2). Conclusion: The coencapsulation of carvedilol/quercetin in nanomicellar with a single dose increases the bioavailability of carvedilol and potentiates its bradycardic effect. While, in chronic treatment, the combination offers greater protection against target organ damage in SHR.