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Eur J Pharmacol. 1997 May 30;327(2-3):195-207.

Tolterodine--a new bladder-selective antimuscarinic agent.

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Medical Department Urology, Pharmacia & Upjohn AB, Uppsala, Sweden.


Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related to an overactive bladder. The aim of the present study was to compare the antimuscarinic properties of tolterodine with those of oxybutynin, in vitro and in vivo. Tolterodine effectively inhibited carbachol-induced contractions of isolated strips of urinary bladder from guinea pigs (K(B) 3.0 nM; pA2 8.6; Schild slope 0.97) and humans (K(B) 4.0 nM; pA2 8.4; Schild slope 1.04) in a concentration-dependent, competitive manner. The affinity of tolterodine was similar to that derived for oxybutynin (K(B) 4.4 nM; pA2 8.5; Schild slope 0.89) in the guinea-pig bladder. Tolterodine (21-2103 nmol/kg (0.01-1 mg/kg); intravenous infusion) was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation in the anaesthetised cat. In contrast, oxybutynin displayed the opposite tissue selectivity. Radioligand binding data showed that tolterodine bound with high affinity to muscarinic receptors in urinary bladder (K(i) 2.7 nM), heart (K(i) 1.6 nM), cerebral cortex (K(i) 0.75 nM) and parotid gland (K(i) 4.8 nM) from guinea pigs and in urinary bladder from humans (K(i) 3.3 nM). Tolterodine and oxybutynin were equipotent, except in the parotid gland, where oxybutynin bound with 8-times higher affinity (K(i) 0.62 nM). Binding data on human muscarinic m1-m5 receptors expressed in Chinese hamster ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits selectivity (10-fold) for muscarinic m3 over m2 receptors. The K(B) value determined for oxybutynin (4.4 nM) in functional studies on guinea-pig bladder correlated better with the binding affinity at muscarinic M2/m2 receptors (K(i) 2.8 and 6.7 nM) than at muscarinic M3/m3 receptors (K(i) 0.62 and 0.67 nM). The tissue selectivity demonstrated for tolterodine in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. However, the combined in vitro and in vivo data on tolterodine and oxybutynin may indicate either that muscarinic M3/m3 receptors in glands are more sensitive to blockade than those in bladder smooth muscle, or that muscarinic M2/m2 receptors contribute to bladder contraction.

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