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 language | English |
|---|---|
| Pages (from-to) | 2035-2044 |
| Number of pages | 10 |
| Journal | Pharmaceutical Research |
| Volume | 22 |
| Issue number | 12 |
| DOIs | |
| State | Published - 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
Cite this
Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics. / Wu, Whei Mei; Buchwald, Peter; Mori, Nobuhiro; Ji, Fubao; Wu, JiaXiang; Bodor, Nicholas.
In: Pharmaceutical Research, Vol. 22, No. 12, 01.12.2005, p. 2035-2044.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics
AU - Wu, Whei Mei
AU - Buchwald, Peter
AU - Mori, Nobuhiro
AU - Ji, Fubao
AU - Wu, JiaXiang
AU - Bodor, Nicholas
PY - 2005/12/1
Y1 - 2005/12/1
N2 - 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.
AB - 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.
KW - Glycopyrrolate
KW - Guinea pig ileum assay
KW - Muscarinic antagonist
KW - Mydriatic effect
KW - Stereoselectivity
UR - http://www.scopus.com/inward/record.url?scp=29244433147&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29244433147&partnerID=8YFLogxK
U2 - 10.1007/s11095-005-8174-z
DO - 10.1007/s11095-005-8174-z
M3 - Article
C2 - 16170596
AN - SCOPUS:29244433147
VL - 22
SP - 2035
EP - 2044
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 12
ER -