title: Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats.
abstract: Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic-pharmacodynamic (PK-PD) modeling.        Male Sprague-Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modeling. 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. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in F 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 F rats.        Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.
authors: Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors: Facundo
authors: F
authors: Bertera
authors: Carla Andrea
authors: CA
authors: Di Verniero
authors: Marcos Alejandro
authors: MA
authors: Mayer
authors: Diego
authors: D
authors: Chiappetta
authors: Fabián
authors: F
authors: Buontempo
authors: Ariel Héctor
authors: AH
authors: Polizio
authors: Carlos Alberto
authors: CA
authors: Taira
authors: Christian
authors: C
authors: Höcht
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077261:Carvedilol; D005632:Fructose; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D011412:Propanolamines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D005632:Fructose