Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects

Müller, P; Flesch, G.; Gasparo, Marc de; Gasparini, Mauro; Howald, H.

doi:10.1007/s002280050317

Cited by 68 publications

(55 citation statements)

References 17 publications

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“…The study has also shown that treatment of normal volunteers with valsartan only, did not affect BP and PWV under standardised conditions, which is in contrast to that reported by Muller et al 15 They treated 16 healthy volunteers with valsartan (200 mg) for 8 days and showed a significant fall in SBP and DBP. The difference in effect of valsartan between the two studies could reflect a different salt intake by the respective volunteers, however racial differences in response to the drug 16 cannot yet be excluded.…”

Section: Discussioncontrasting

confidence: 66%

Effect of angiotensin II on pulse wave velocity in humans is mediated through angiotensin II type 1 (AT1) receptors

2002

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The objective of this study was to examine the effect of angiotensin II (Ang II) and angiotensin II type 1 (AT 1 ) receptor blockade on pulse wave velocity (PWV) in healthy humans. We studied nine young male volunteers in a double-blind randomised crossover design. Carotidfemoral PWV (an index of arterial stiffness) was measured by using a Complior  machine. Subjects were previously treated for 3 days with once-daily dose of either a placebo or valsartan 80 mg. On the third day, they were infused with either placebo or 5 ng/kg/min of Ang II over 30 min. Subjects thus received placebo capsule + placebo infusion (P), valsartan + placebo infusion (V), placebo + Ang II infusion (A), and valsartan + Ang II infusion (VA) combinations. Heart rate (HR), blood pressure and PWV were recorded at baseline and then every 10 min during infusion and once after the end of infusion. There were significant increases in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) with A compared with

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Section: Discussioncontrasting

confidence: 66%

Effect of angiotensin II on pulse wave velocity in humans is mediated through angiotensin II type 1 (AT1) receptors

2002

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“…8 Protein binding of valsartan is high (94 -97%, mainly to albumin), 14,15,147 and its Vd is 17 L. 14,15,145 The Cl T of valsartan is 37 mL/min (Table 6b), and plasma elimination t . is in the range of 6-10 h. 14,15,[144][145][146]148 The drug does not accumulate significantly (Ͻ20%) after repeated dosing. 8,14,15 Valsartan is eliminated mainly by biliary excretion as unchanged drug in faeces (Table 7; 80-85%).…”

Section: S79mentioning

confidence: 99%

“…8,14,15,144,145 Oral bioavailability (Table 6a) is about 19% (range 10-35%) if given as a capsule, but 39-51% if given as a solution. 8,14,15,145,146 The T max of valsartan is 2-4 h after the administration of a capsule; 8,14,15 the absorption is more rapid if the drug is given as a solution (T max = 1 h). 145 Food decreases C max by 50% and AUC by 40%.…”

Section: S79mentioning

confidence: 99%

“…145,148 Valsartan is not metabolised by the cytochrome P450 enzymes, 14,15 but is converted to inactive compounds (15-20% of the dose), 14,15,145 with only 9% in the circulation. 146,148 Pharmacokinetics of angiotensin receptor blockers in special populations (Table 8) No gender differences are observed in the pharmacokinetic parameters of candesartan, 12,14,15 eprosartan, 11,149 EXP3174, 14,15 irbesartan, 6,14,15,32,41,150 and valsartan. 14,15 But, female subjects were found to have twice as high C max for losartan 14,15 and telmisartan 15 as in males; the AUC of telmisartan is also higher (250%) in females than in males.…”

Section: S79mentioning

confidence: 99%

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Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

2000

J Hum Hypertens

284

215

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Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy.The ARBs specifically block the interaction of angiotensin II at the AT 1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacokinetics After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels ‫؍‬ 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavaila...

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“…HPLC with UV detectors are easy to handle. The HPLC methods with photodiode array (PDA) and UV detectors have also been reported for the extraction of valsartan from the human plasma [1,18,19] .…”

Section: Several Bioanalytical Methods Have Been Reportedmentioning

confidence: 99%

Statistical Optimization of Extraction Process for the Quantification of Valsartan in Rabbit Plasma by a HPLC Method

Reddy¹

2017

ijps

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This article describes a high performance liquid chromatography method for determination of valsartan in rabbit plasma. The method was statistically optimized, developed and validated as per United States of Food and Drug Administration guidelines. The solvent deproteination technique was opted for the extraction of valsartan from rabbit plasma. Full factorial design was used for the optimization of an extraction method. The main effect of deproteinating agent, volume of deproteinating agent, speed of centrifugation and time of centrifugation was found to be significant at P<0.0001 on all the responses. After deproteinization, the drug was analysed on a C 18 column using 20 mM ammonium formate:acetonitrile (58:42 v/v) as the mobile phase with a flow rate of 0.9 ml/min. The standard calibration curve was constructed in the concentration range of 75 ng/ml to 4.0 µg/ml and linearity was found to be 0.9989. Losartan was used as the internal standard. The retention time of valsartan and the internal standard was found to be 11.394 and 6.343 min, respectively. No interference peak was perceived. From the accuracy results, the relative error was found between 0.99 and 13.01% and relative standard deviation was between 1.43 and 12.19%. The percent relative standard deviation of intra-day and inter-day precision was found to be less than 15%. Limit of detection and limit of quantitation were found to be 22.00 and 66.67 ng/ml, respectively. From pharmacokinetic applications, the peak plasma concentration (C max ) of valsartan oral suspension was found to be 1092.67±39.62 ng/ml at 0.67±1.24 h. The half-life and area under the curve were found to be 19.92±10.28 h and 8393.35±131.14 ng/ml, respectively. The high performance liquid chromatography method was successfully demonstrated as rapid and sensitive method which can be used as an alternative for the analysis of valsartan in plasma samples.

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Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects

Cited by 68 publications

References 17 publications

Effect of angiotensin II on pulse wave velocity in humans is mediated through angiotensin II type 1 (AT1) receptors

Effect of angiotensin II on pulse wave velocity in humans is mediated through angiotensin II type 1 (AT1) receptors

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

Statistical Optimization of Extraction Process for the Quantification of Valsartan in Rabbit Plasma by a HPLC Method

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