Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man

Beaumont, Kevin; Cussans, Nigel J.; Nichols, D. J.; Smith, Dennis A.

doi:10.1080/004982598239768

Cited by 36 publications

(34 citation statements)

References 3 publications

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“…Several pharmacological studies have demonstrated that darifenacin has no Ca 2+ -channel antagonist action [11,14,16]. In addition, it has been shown to exhibit favorable selectivity for the bladder compared with the salivary glands and heart in vivo, while atropine is nonselective [14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Effects of Darifenacin on Human Isolated Urinary Bladder

et al. 2003

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Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl₂- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA₂values) at the muscarinic M₃ receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10^–6 mol/l, did not inhibit the KCl- and CaCl₂-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10^–5 mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10^–9–10^–6 mol/l), propiverine (10^–8– 10^–5 mol/l), oxybutynin (10^–8–10^–5 mol/l) and atropine (10^–9–10^–6 mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca²⁺ channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M₃ receptor and support its use as a treatment for overactive bladder.

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Section: Introductionmentioning

confidence: 99%

Pharmacological Effects of Darifenacin on Human Isolated Urinary Bladder

et al. 2003

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“…UK-148,993, UK-73,689, and UK-88,862 are the three main circulating darifenacin metabolites, of which only UK-148,993 is said to have signifi cant antimuscarinic activity. UK-148,993 is formed primarily through CYP2D6 and CYP3A4 [44]. Because only small amounts of unchanged darifenacin is excreted via urine, most of the metabolites formed are inactive.…”

Section: Darifenacinmentioning

confidence: 99%

Urothelial effects of oral agents for overactive bladder

Andersson

Füllhase²,

Soler³

2008

Curr Urol Rep

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The cholinergic system of the bladder includes muscarinic receptors distributed to detrusor myocytes and structures within mucosa including bladder afferent (sensory) nerves. The receptors have been shown to be involved in afferent signaling from the bladder, but it has not been established to what extent effects on this mucosal signaling pathway contribute to the therapeutic efficacy of the clinically used antimuscarinics. Mucosa can be influenced by antimuscarinics via the bloodstream. However, some antimuscarinics and their active metabolites are excreted in urine in amounts that may affect the mucosal muscarinic receptors from the luminal side. This has not yet been demonstrated to imply superior clinical efficacy. Nevertheless, mucosal afferent signaling pathways are therapeutically interesting targets that should be further explored.

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“…MAA: methacrylic acid 4-VP: 4-vinylpyridine [14] under clinical development for urinary incontinence [ 15,16]. In either case, the lower limit of quantification is often determined not by the limit of detection (at, say, a signal-to-noise ratio of 5) but by interference by co-eluting endogenous material.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and properties of molecular imprints of darifenacin: The potential of molecular imprinting for bioanalysis

Venn

Goody

1999

Chromatographia

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A molecularly imprinted polymer has been developed which subsequently demonstrated an ability to selectively retain darifenacin (UK-88,525-S) from aqueous acetonitrile when used as a stationary phase in HPLC columns and as a packing in solid-phase extraction cartridges. The imprinted polymer is applicable to a wide range of analytical methods including extraction from plasma, purification ofradiolabelled UK-88,525, chiral separations and separation of metabolites and structural analogues. The polymer is able to extract darifenacin directly from a protein-precipitated human plasma/ acetonitrile (1:1 v/v) mixture with 100 % recovery. The imprinted polymer can also effect a repurification of 14C-labelled darifenacin. The drawbacks of molecular imprints for ultra-trace bioanalysis (in the sub-nanogram/mL range) are discussed. These centre on the difficulty of removing all the template from the polymer and the consequent effects of template bleed on assay precision and accuracy when used as solid-phase extraction cartridges. Possible solutions to this problem are considered. 0.~. NH2~"'~,, 0 9 ) 9 indicates a chiral centre Figure 1 Structure of darifenacin

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Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man

Cited by 36 publications

References 3 publications

Pharmacological Effects of Darifenacin on Human Isolated Urinary Bladder

Pharmacological Effects of Darifenacin on Human Isolated Urinary Bladder

Urothelial effects of oral agents for overactive bladder

Synthesis and properties of molecular imprints of darifenacin: The potential of molecular imprinting for bioanalysis

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