Abstract
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 μmol/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 (Kd) for specific binding of [N-methyl-3H]scopolamine ([3H]NMS). In addition, the intravesical instillation of M-2 produced a significant increase in Kd for specific [3H]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 (Cmax) after the oral administration of propiverine at doses of 24.8, 74.3, and 248 μmol/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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033233.
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ABBREVIATIONS:
- M-1
- 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide
- M-2
- 1-methyl-4-piperidyl benzilate N-oxide
- [3H]NMS
- [N-methyl-3H]scopolamine methyl chloride
- Kd
- apparent dissociation constant
- Bmax
- maximal number of binding sites
- HPLC
- high-performance liquid chromatography
- Ki
- inhibition constant
- AUC
- area under the time-concentration curve
- Cmax
- maximal plasma concentration
- T/P
- tissue/plasma.
- Received March 14, 2010.
- Accepted May 18, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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