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We characterized contribution of N-oxide metabolites [1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (M-1) and 1-methyl-4-piperidyl benzilate N-oxide (M-2)] to the binding of muscarinic receptors in relation to the pharmacokinetics of propiverine in rats. The in vitro muscarinic receptor binding activity of M-2 was equipotent to that of propiverine, whereas M-1 was much less active. After the oral administration of propiverine (24.8-248 micromol/kg), there was relatively selective and longer-lasting binding of muscarinic receptors in the rat bladder compared with the submaxillary gland as shown by a significant increase in the apparent dissociation constant (K(d)) for specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS). In addition, the intravesical instillation of M-2 produced a significant increase in K(d) for specific [(3)H]NMS binding in the rat bladder. Extremely high concentrations of M-1 and M-2 were detected in plasma after the oral administration of propiverine. The concentration of unbound M-2 was much higher than that of M-1 and propiverine in the rat plasma. The sum of maximal plasma unbound propiverine equivalents (C(max)) after the oral administration of propiverine at doses of 24.8, 74.3, and 248 micromol/kg was 66.0, 303, and 509 nM, respectively. The sum of corresponding area under the time-concentration curve from 0 to 12 h was 194, 2123, and 4645 nM . h, respectively. In fact, the unbound concentration of M-2 comprised more than 90% of sum of unbound propiverine equivalents in the plasma. After oral treatment with propiverine, the bladder showed the highest concentration of M-2, indicating specific distribution of this metabolite into the target organ. Thus, M-2 may contribute greatly to the relatively selective and long-lasting occupation of bladder muscarinic receptors after oral administration of propiverine.

The muscarinic receptor antagonist propiverine used for therapy of overactive bladder undergoes first pass metabolism, leading to several active metabolites, which affect muscarinic receptors and L-type Ca(2+) channels with different potencies. M-5, the major metabolite in blood, and M-6 can be synthesized as cis- and trans-isomers. We systematically investigated the pharmacodynamic profiles of the isomers on detrusor contractile function. In murine and porcine detrusor, the effects of the derivatives were examined on contractions induced by electric field stimulation (EFS), cumulatively increasing concentrations of carbachol or high KCl concentration. EFS contractions were concentration-dependently reduced by the M-5 and M-6 isomers although to a different extent. M-5(cis) was slightly more potent than M-5(trans), but the differences did not reach statistical significance. M-6(cis) was significantly more potent than M-6(trans). Responses to carbachol were antagonized by all compounds due to rightward shifts of the concentration-response curves, but only M-5(trans) also significantly reduced the maximum response. pK (B) values obtained with Schild plot analysis indicated slightly higher potency for M-6(cis) than M-6(trans). Ca(2+) influx-dependent contractions elicited by K(+) depolarization were less impaired by low concentrations of the M-6 isomers, but strongly suppressed by 100 microM of the M-5 isomers, suggesting an additional effect of the two M-5 isomers on Ca(2+) influx. All investigated isomers of M-5 and M-6 are biologically active in reducing detrusor contraction in animal tissue. While M-5( cis,) M-6(cis), and M-6(trans) possess surmountable or partially surmountable antagonistic properties at muscarinic receptors, M-5(trans) is a strong non-competitive antagonist. However, at higher concentration ranges, all four compounds seem to have additional effects on Ca(2+) influx.

Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects., Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively., Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure., Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

The aim of this study was to evaluate the effects of a novel antimuscarinic agent, Lu 25-109, a partial M1 receptor agonist, and M2/M3 receptor antagonist in human and pig detrusor to establish its affinity for muscarinic receptors in human detrusor and parotid gland and to compare the results with those obtained with oxybutynin. Effects on the detrusor were determined as regards the ability to inhibit carbachol-induced contractions and contractions induced by electrical field stimulation (EFS). Radioligand binding studies were performed to assess the ability to displace quinuclidinyl benzilate (3H-QNB) from muscarinic receptors in the detrusor and parotid gland. Lu 25-109 produced a concentration-dependent rightward shift of the concentration-response curves for carbachol in both human and pig detrusor, the pK(b) values being 6.2+/-0.1 (n=6) and 5.8+/-0.3 (n=6). Corresponding values for oxybutynin were 7.9+/-0.1 (n=7) and 7.8+/-0.1 (n=6). Contractions induced by EFS in human detrusor were almost completely inhibited by 100 micromol/L Lu 25-109 (84+/-4%; n=4). In contrast, EFS-induced contractions in pig detrusor were less sensitive to Lu 25-109, resulting in a final inhibition of 32+/-6% (n=9) with the highest concentration used (100 micromol/L). This difference in effect between human and pig detrusor was not observed with oxybutynin. Radioligand binding experiments demonstrated a small difference in affinity for Lu 25-109 in the parotid gland compared with the bladder, the pKi values being 6.2+/-0.1 versus 6.5+/-0.1 (n=4). Corresponding values for oxybutynin were 8.5+/-0.1 versus 8.2+/-0.1 (n=4). The results show that Lu 25-109 competitively and effectively antagonizes carbachol-induced contractions and contractions induced by EFS in human detrusor muscle. Even if Lu 25-109 were less potent than oxybutynin, it has an effect profile that makes it of interest to test its ability to counteract bladder overactivity in humans., (Copyright 2002 Wiley‐Liss, Inc.)