Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics

Whei Mei Wu, Peter Buchwald, Nobuhiro Mori, Fubao Ji, JiaXiang Wu, Nicholas Bodor

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Abstract

Purpose. This study was conducted to evaluate the zwitterionic common metabolite of a novel series of N-substituted soft analogs of glycopyrrolate both as racemates and as 2R isomers. Methods. Activities were assessed using both in vitro (receptor binding assay, guinea pig ileum pA 2 assay) and in vivo techniques (rabbit mydriatic response, rat cardiac effects). Pharmacokinetic characterizations in rats were also performed. Results. The metabolite was highly water-soluble and very stable in buffer solutions as well as in rat biological media. Following i.v. administration in rats, it was very rapidly eliminated, mainly through renal excretion with a half-life of about 10 min. Receptor binding and guinea pig ileum assays indicated this metabolite as more than 1 order of magnitude less active than its parent soft drugs or glycopyrrolate. Moderate M3/M2 muscarinic receptor subtype selectivity was observed, further reducing the likelihood of cardiac side effects. The metabolite showed to some extent mydriatic effect and protective effect against carbachol-induced bradycardia, but of much shorter durations than glycopyrrolate; it had, however, no effect on resting heart rate. Conclusions. N-Substituted zwitterionic metabolites retain some, but only considerably reduced activity of their parent quaternary ammonium ester soft anticholinergic drugs, and they are very rapidly eliminated from the systemic circulation. They are suitable for their assigned role within the framework of inactive metabolite-based soft anticholinergic design.

Original languageEnglish
Pages (from-to)2035-2044
Number of pages10
JournalPharmaceutical Research
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2005

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Keywords

  • Glycopyrrolate
  • Guinea pig ileum assay
  • Muscarinic antagonist
  • Mydriatic effect
  • Stereoselectivity

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

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