Darifenacin HBr (Synonyms: UK 88525-04)

DarifenacinHBr(UK88525) is a selective M3 muscarinic receptor antagonist with pKi of 8.9 [1].

Themuscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or themuscarinic 3, is amuscarinic acetylcholine receptorencoded by the human geneCHRM3. The M3muscarinic receptors are widely expressed in tissues such as smooth muscles, theendocrineglands, the exocrine glands, lungs and pancreas.M3 muscarinic receptor is involved in smooth muscle contraction and increases glandular secretions [2].

In vitro: In a model of the blood-brain barrier (BBB) and blood-ocular barrier (BOB), Darifenacin was a substrate for the P-gp drug efflux transporter. Darifenacin increased ATPase activity in a concentration-dependent manner in P-gp membranes with an ED50 value of 1.6 µM.Darifenacin treatment (100 nM) showed a significantly greater permeability for darifenacin in the basolateral to apical direction resulting in an efflux ratio in BBMEC monolayers of approximately 2.6 [3].

In vivo: Darifenacin dose-dependently inhibited the amplitude of volume-induced bladder contractions(VIBCAMP), producing 35% inhibition at dose of 283.3 nmol/kg and maximal inhibition of approximately 50–55%[1].In female Sprague-Dawley rats, administration of darifenacin (0.1 mg/kg i.v.) reduced bladder afferent activity in Aδ and C fibers. The decrease of afferent spikes in C fibers was more pronounced than that in Aδ fibers [3]. In patients with overactive bladder (OAB), darifenacin at a dose of 7.5 mg and 15 mg exihibited a rapid onset of effect, with significant improvement compared with placebo being seen for most parameters at the first clinic visit (week 2). Darifenacin administration (7.5 mg and 15 mg, daily) reduced the number of incontinence episodes per week from baseline by 67.7% and 72.8% respectively compared with 55.9% with placebo in patients with overactive bladder (OAB). Darifenacin (7.5 mg and 15 mg, daily) also showed significantly superior to placebo for improvements in micturition frequency, bladder capacity, frequency of urgency, number of incontinence episodes and severity of urgency leading to a change in clothing or pads in patients with overactive bladder (OAB) [4].

References:
[1]. Hegde SS1,Choppin A,Bonhaus D,Briaud S,Loeb M,Moy TM,Loury D,Eglen RM.Functional role of M2 andM3muscarinic receptorsin the urinary bladder of rats in vitro and in vivo.Br J Pharmacol.1997 Apr;120(8):1409-18.
[2]. Brann MR1,Ellis J,Jrgensen H,Hill-Eubanks D,Jones SV. Muscarinicacetylcholinereceptorsubtypes: localization and structure/function.Prog Brain Res.1993;98:121-7.
[3]. Miller DW1,Hinton M,Chen F.Evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers. Neurourol Urodyn.2011 Nov;30(8):1633-8. doi: 10.1002/nau.21110. Epub 2011 Aug 8.
[4]. Haab F1,Stewart L,Dwyer P.Darifenacin, anM3selectivereceptorantagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol.2004 Apr;45(4):420-9; discussion 429.