Darifenacin Urinary Incontinence [1518

Country of origin US

Originator: Pfizer

First introduction Germany

Introduced by: Novartis

Trade name Enablex; Emselex

CAS registry no 133099-04-04

Molecular weight 426.55

darifenacin demonstrates greater effect on tissues in which the predominant receptor type is M3 rather than Ml or M2. In vitro darifenacin inhibits carbachol-induced contractions with greater potency in isolated guinea-pig bladder (M3) than in guinea-pig atria (M2) or dog saphenous vein (Ml). In animal models, it shows greater selectivity for inhibition of detrusor contraction over salivation or tachycardia. The synthesis of darifenacin involves the coupling of 5-(2-bromoethyl)-2, 3-dihydrobenzofuran with 3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine as a key step. The latter intermediate is prepared from 3-(R)-hydroxypyrrolidine in a five-step sequence involving N-tosylation, Mitsunobu reaction to introduce a tosy-loxy group in the 3-position with stereochemical inversion, anionic alkylation with diphenylacetonitrile, cleavage of the N-tosyl protecting group with HBr, and conversion of the cyano group to a carboxamide. Darifenacin is supplied as a controlled release formulation, and the recommended dosage is 7.5 mg once, daily. Darifenacin is rapidly and completely absorbed from the GI tract after oral administration, with maximum plasma levels achieved after about 7 h. The elimination half-life is approximately 3 h, but because of the controlled release characteristics of the formulation, the drug is suitable for once-daily dosing. Steady-state plasma levels are achieved within 6 days of commencing treatment. Darifenacin exhibits high-protein binding (98%), a volume of distribution of 163 L, and a clearance of 40L/h. It has low oral bioavailability (15-19%) due to extensive first-pass metabolism by CYP3A4 and CYP2D6, but this can be saturated after multiple administrations. The major circulating metabolites are produced by monohydroxylation and N-dealkylation; however, none contribute significantly to the overall clinical effect of darifenacin. Approximately 58% of the dose is excreted in urine and 44% in feces; only a small percentage (3%) of the excreted dose is unchanged dari-fenacin. The clinical efficacy of darifenacin was established in three randomized, double-blind, placebo-controlled trials (n = 1059). For inclusion in these trials, patients had a six-month history of overactive bladder with at least eight micturitions per day, one episode of urinary urgency per day, and five episodes of urge urinary incontinence per week. In each trial, darifenacin reduced urinary incontinence by 8-11 episodes per week versus baseline (55-70%). However, due to a strong placebo response, this represented a decrease of only 2-4 episodes per week versus placebo (9-23%, ^<0.05). The main adverse events associated with dari-fenacin included dry mouth, constipation, dyspepsia, and urinary tract infection.

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