Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics.
OBJECTIVE
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 pA2 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.
Wu
Whei-Mei
WM
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Buchwald
Peter
P
Mori
Nobuhiro
N
Ji
Fubao
F
Wu
JiaXiang
J
Bodor
Nicholas
N
D000287:Administration, Topical; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000517:prevention & control; D002217:Carbachol; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D018721:Muscarinic Agonists; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009184:Mydriatics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet
D018680:Cholinergic Antagonists; D018721:Muscarinic Agonists; D009184:Mydriatics; D011976:Receptors, Muscarinic; D012996:Solutions; D002217:Carbachol