5-hydroxymethyl tolterodine (PNU 200577) is a potent and selective muscarinic receptor antagonist with a Kb and a pA2 of 0.84 nM and 9.14, respectively. 5-hydroxymethyl tolterodine (PNU 200577) is a major pharmacologically active metabolite of tolterodine. In vitro, PNU-200577 prevented carbachol-induced contraction of guinea-pig isolated urinary bladder strips in a competitive and concentration-dependent manner. In vivo, PNU-200577 was significantly more potent at suppressing acetylcholine-induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID50=15 and 40 nmol/kg, respectively). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic m1-m5 receptors, 5-hydroxymethyl tolterodine (PNU 200577) was not selective for any muscarinic receptor subtype. Thus, 5-hydroxymethyl tolterodine (PNU 200577) is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in vitro. The results of this study clearly indicate that 5-hydroxymethyl tolterodine (PNU 200577) contributes to the therapeutic action of tolterodine, in view of its high antimuscarinic potency, similar serum concentration and lower degree of protein binding.
| Cell Experiment | |
|---|---|
| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
|---|---|
| Animal models | Male guinea-pigs |
| Formulation | Saline |
| Dosages | 2 nmol/kg -203 nmol/kg |
| Administration | Administered via i.v. |
| Molecular Weight | 341.49 |
| Formula | C22H31NO2 |
| CAS Number | 207679-81-0 |
| Form | Solid |
| Solubility (25°C) | DMSO 58 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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