1.Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits.
Serebruany VL1, Malinin AI, Lowry DR, Sane DC, Webb RL, Gottlieb SO, O'Connor CM, Hennekens CH. J Cardiovasc Pharmacol. 2004 May;43(5):677-84.
Valsartan selectively blocks angiotensin II binding to the AT1 receptor. ince platelet activation plays a key role in the pathogenesis of vascular disease, and because AT1 receptors are present on the platelet surface, we assessed the in vitro effects of valsartan and its metabolite, valeryl 4-hydroxy valsartan (V4HV), on platelets in 30 subjects with multiple risk factors for cardiovascular disease. Platelet characteristics in blood samples pretreated and incubated with 10 nmol to 100 micromol concentrations of valsartan and V4HV were assessed by aggregometry, rapid platelet analyzers, and by flow cytometry. Pretreatment of blood with valsartan and V4HV resulted in inhibition of conventional plasma (ADP, P = 0.0001, valsartan; epinephrine, P = 0.0001, V4HV) and whole blood collagen-induced (P = 0.01, valsartan; P =.0001, V4HV) platelet aggregation. Closure time was delayed (P = 0.02, valsartan; P = 0.03, 4VHV), indicating platelet inhibition in whole blood under high shear conditions.
2.Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats.
Takai S1, Jin D, Aritomi S, Niinuma K, Miyazaki M. Hypertens Res. 2013 Apr;36(4):342-8. doi: 10.1038/hr.2012.187. Epub 2012 Nov 29.
Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group.
3.Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose.
Waldmeier F1, Flesch G, Müller P, Winkler T, Kriemler HP, Bühlmayer P, De Gasparo M. Xenobiotica. 1997 Jan;27(1):59-71.
1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity.
4.Optimization via experimental design of an SPE-HPLC-UV-fluorescence method for the determination of valsartan and its metabolite in human plasma samples.
Iriarte G1, Ferreirós N, Ibarrondo I, Alonso RM, Maguregi MI, Gonzalez L, Jiménez RM. J Sep Sci. 2006 Oct;29(15):2265-83.
A chemometric approach was applied for the optimization of the extraction and separation of the antihypertensive drug valsartan and its metabolite valeryl-4-hydroxy-valsartan from human plasma samples. Due to the high number of experimental and response variables to be studied, fractional factorial design (FFD) and central composite design (CCD) were used to optimize the HPLC-UV-fluorescence method. First, the significant variables were chosen with the help of FFD; then, a CCD was run to obtain the optimal values for the significant variables. The measured responses were the corrected areas of the two analytes and the resolution between the chromatographic peaks. Separation of valsartan, its metabolite valeryl-4-hydroxy-valsartan and candesartan M1, used as internal standard, was made using an Atlantis dC18 100 mm x 3.9 mm id, 100 angstroms, 3 microm chromatographic column. The mobile phase was run in gradient elution mode and consisted of ACN with 0.