| In Vitro | In vitro activity: Solifenacin succinate is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The affinity constants (pKi) of solifenacin for recombinant human muscarinic M1, M2 and M3 receptors are 7.6, 6.9 and 8.0, respectively. Hence, the muscarinic M3 receptor subtype selectivity of solifenacin over the muscarinic M2 receptor subtype is readily apparent, but is only marginal over the muscarinic M1 receptor subtype. In the same study, solifenacin and oxybutynin inhibit muscarinic M3 receptor-mediated intracellular Ca2+ mobilization in bladder smooth muscle cells isolated from guinea pigs and in submandibular gland cells isolated from mice.
Kinase Assay: Solifenacin is a novel muscarinic receptor antagonist with pKis of 7.6±0.056, 6.9±0.034 and 8.0±0.021 for M1, M2 and M3 receptors, respectively.
Cell Assay: In radioligand receptor binding assay, the Ki values of solifenacin for human muscarinic M1, M2, M3, M4and M5receptors were 26, 170, 12, 110 and 31 nM, respectively. In isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pA2value of 7.44±0.09.In bladder smooth muscle cells and salivary gland cells isolated from rats, solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular Ca2+levels in a concentration-dependent manner. ThepKi was 8.12 for bladder smooth muscle cells, 3.6-fold more potent than that for salivary gland cells (pKi=7.57). |
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| In Vivo | In anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland. In anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure.In healthy young men, multidose study evaluated doses. In the single-dose of solifenacin succinate (5-, 10-, 20-, and 30-mg), mean time to maximal concentration and elimination half-life ranged from 3.3 to 4.8 and from 40.2 to 57.6 hours, respectively.In the multidose study, the ranges were 2.9 to 5.8 and 45.0 to 64.8, respectively. The single-dose administration was well tolerated. The common adverse events were dry mouth, blurred vision, and headache. Solifenacin reduces bladder responses by 40% at a dose of 210 nmol/kg (0.1 mg/kg) and abolishes them at 2100 nmol/kg (1 mg/kg). In contrast, its inhibitory effects on salivary and cardiac responses are only slight at 630 nmol/kg (0.3 mg/kg), and reach 66% and 49%, respectively, at 2100 nmol/kg (1 mg/kg). At doses of 63 and 210 nmol/kg (0.03 and 0.1 mg/kg), Solifenacin slightly increases saliva secretion. Solifenacin (0.01 to 0.3 mg/kg i.v.) dose-dependently increases bladder capacity and voided volume at doses of 0.03 mg/kg i.v. or more, but does not affect residual volume or micturition pressure at any dose tested |
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