Protein Binding in Plasma of Valsartan, a New Angiotensin II Receptor Antagonist

Colussi, Danielle; Parisot, Carole; Rossolino, Maria L.; Brunner, Linda A.; Lefèvre, Gilbert

doi:10.1002/j.1552-4604.1997.tb04783.x

Cited by 44 publications

(20 citation statements)

References 7 publications

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“…According to the manufacturer's interview form, the maximum plasma concentration (C max ) and AUC are directly proportional to the dose in Japanese healthy male subjects. After oral administration of 160 mg of valsartan, the C max is 12 M and the plasma unbound fraction is 5 to 7% (Colussi et al, 1997), indicating that the unbound plasma concentration of valsartan is 0.60 to 0.84 M. This value is lower than the K m values obtained from OATP-expressing systems and human hepatocytes. This is consistent with the fact that valsartan exhibits linear pharmacokinetics over the clinical dose range.…”

Section: Discussionmentioning

confidence: 61%

Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

Yamashiro¹,

Maeda²,

Hirouchi³

et al. 2006

Drug Metabolism and Disposition

184

100

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ABSTRACT:Valsartan is a highly selective angiotensin II AT1-receptor antagonist for the treatment of hypertension. Valsartan is mainly excreted into the bile in unchanged form. Because valsartan has an anionic carboxyl group, we hypothesized that a series of organic anion transporters could be involved in its hepatic clearance. In this study, to identify transporters that mediate the hepatic uptake and biliary excretion of valsartan and estimate the contribution of each transporter to the overall hepatic uptake and efflux, we characterized its transport using transporter-expressing systems, human cryopreserved hepatocytes, and Mrp2-deficient Eisai hyperbilirubinemic rats (EHBRs). Valsartan was significantly taken up into organic anion-transporting polypeptide (OATP) 1B1 (OATP2/OATP-C)-and OATP1B3 (OATP8)-expressing HEK293 cells. We also observed saturable uptake into human hepatocytes. Based on our estimation, the relative contribution of OATP1B1 to the uptake of valsartan in human hepatocytes depends on the batch, ranging from 20 to 70%. Regarding efflux transporters, the ratio of basalto-apical transcellular transport of valsartan to that in the opposite direction in OATP1B1/MRP2 (multidrug resistance-associated protein 2) double transfected cells was the highest among the three kinds of double transfectants, OATP1B1/MRP2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance proteinexpressing MDCKII cells. We observed saturable ATP-dependent transport into membrane vesicles expressing human MRP2. We also found that the elimination of intravenously administered valsartan from plasma was markedly delayed, and the biliary excretion was severely impaired in EHBR compared with normal Sprague-Dawley rats. These results suggest that OATP1B1 and OATP1B3 as the uptake transporters and MRP2 as the efflux transporter are responsible for the efficient hepatobiliary transport of valsartan.

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Section: Discussionmentioning

confidence: 61%

Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

Yamashiro¹,

Maeda²,

Hirouchi³

et al. 2006

Drug Metabolism and Disposition

184

100

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“…Valsartan is highly bound to serum proteins (95%), mainly albumin (Colussi et al, 1997), resulting in a V d of 17 liters , indicating that valsartan does not distribute into tissues extensively. In contrast to telmisartan, plasma protein binding here apparently limits tissue penetration.…”

Section: B Distributionmentioning

confidence: 99%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

Michel

Foster

Brunner

et al. 2013

Pharmacological Reviews

249

224

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“…14,15 The C max and AUC increase linearly with increasing dose (range 80-320 mg). 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.…”

Section: S79mentioning

confidence: 99%

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

2000

J Hum Hypertens

289

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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Protein Binding in Plasma of Valsartan, a New Angiotensin II Receptor Antagonist

Cited by 44 publications

References 7 publications

Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

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

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