Candesartan in heart failure

Ripley, Toni L.; Chonlahan, Jennifer; Germany, Robin

doi:10.2147/ciia.2006.1.4.357

Cited by 15 publications

(8 citation statements)

References 42 publications

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“…It is used in the treatment of hypertension and congestive heart failure [161][162][163]. Candesartan is liberated from its ester racemic prodrug, candesartan cilexitil, by presystemic hydrolysis in the intestinal wall [164].…”

Section: Candesartanmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Candesartanmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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“…The antihypertensive effect with CC monotherapy increases with the dose but never exceeds 60% at a daily dose of 16 mg. However, at doses up to 32 mg day, antihypertensive effect did not increase further [9,[11][12][13][14].…”

Section: Clinical Backgroundmentioning

confidence: 99%

An Explicit Review on Quantitative Estimation of Candesartan Cilexetil Employing Various Analytical Techniques

Shantanu¹,

yopadhyay²,

Bhuria³

et al. 2013

Pharmaceut Anal Acta

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“…Candesartan (CDS) is a potent and selective angiotensin II type 1 (AT 1 ) receptor blocker, which has widely been used orally in patients with hypertension, kidney disease and heart failure [1,2]. CDS lowers blood pressure through blockade of the renin-angiotensin-aldosterone system [3].…”

Section: Introductionmentioning

confidence: 99%

Transport characteristics of candesartan in human intestinal Caco‐2 cell line

Zhou

Chen

et al. 2009

Biopharm & Drug Disp

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The intestinal absorptive characteristics and the efflux mechanisms of candesartan (CDS), a novel angiotensin II type 1 receptor blocker, were investigated. The Caco-2 cells were used as models of the intestinal mucosa to assess uptake and transport of CDS. The determination of CDS was performed by HPLC-Flu. In the Caco-2 cells, the uptake and absorptive transport of CDS were pH-independent (in the pH range 6.0-8.0). Passive membrane diffusion dominates the absorptive transport behavior of CDS across Caco-2 cells, while secretory transport was a concentration-dependent and saturable process. In the presence of cyclosporin A and verapamil, potent inhibitors of P-glycoprotein (P-gp), the P(ratio) decreased from 3.8 to 2.3 and 1.8, respectively, and permeation of apical to basolateral was enhanced. Overall, the current study suggests that efflux transporters are capable of mediating the absorption and secretion of CDS, and they may play significant roles in limiting the oral absorption of CDS.

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Candesartan in heart failure

Cited by 15 publications

References 42 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

An Explicit Review on Quantitative Estimation of Candesartan Cilexetil Employing Various Analytical Techniques

Transport characteristics of candesartan in human intestinal Caco‐2 cell line

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