Comparison of the antimuscarinic and antispasmodic actions of racemic oxybutynin and desethyloxybutynin and their enantiomers with those of racemic terodiline.

Racemic oxybutynin (CAS 1508-65-2) is used clinically to treat urinary incontinence and reportedly undergoes N-deethylation to metabolites R- and/or S-desethyloxybutynin. To assess the role of these metabolites in the therapeutic effects of oxybutynin, the antimuscarinic and antispasmodic effects of RS-, R- and S-oxybutynin, RS-, R- and S-desethyloxybutynin and, for comparative purposes, RS-terodiline (CAS 7082-21-5) on isolated strips of guinea pig bladder, were examined. All of these compounds exhibited antimuscarinic activity: they competitively antagonized carbachol-induced contractions, with mean pA2 values (+/- S.E.) of 8.91 +/- 0.20, 8.80 +/- 0.27, 7.09 +/- 0.13, 8.55 +/- 0.32, 9.04 +/- 0.32, 7.31 +/- 0.35 and 6.77 +/- 0.22, respectively. Consistent with an antispasmodic action, all of the compounds produced similar inhibition of potassium-induced contraction; the mean IC50 values for reducing responses to 137.7 mmol/l potassium were between 2.22 and 5.68 mumol/l. Thus, RS- and R-oxybutynin and RS- and R-desethyloxybutynin exhibited high antimuscarinic activity relative to their antispasmodic activity, while S-oxybutynin, S-desethyloxybutynin and RS-terodiline exhibited relatively weak antimuscarinic activity. It is concluded that deethylation of oxybutynin to desethyloxybutynin does not appreciably alter its antimuscarinic or antispasmodic activity and that R- and/or S-desethyloxybutynin probably contribute significantly to the pharmacological properties of oxybutynin in humans. In addition, since the relative potency of the antimuscarinic-to-antispasmodic actions of S-oxybutynin was equivalent to that of RS-terodiline, S-oxybutynin deserves consideration for development as a single-enantiomer drug for the treatment of urinary incontinence. It may produce the same beneficial therapeutic effects as both RS-terodiline and RS-oxybutynin but, like RS-terodiline, produce a lower incidence of antimuscarinic side-effects than seen with RS-oxybutynin.
AuthorsE R Smith, S E Wright, G Aberg, Y Fang, J R McCullough
JournalArzneimittel-Forschung (Arzneimittelforschung) Vol. 48 Issue 10 Pg. 1012-8 (Oct 1998) ISSN: 0004-4172 [Print] GERMANY
PMID9825119 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Butylamines
  • Mandelic Acids
  • Parasympatholytics
  • terodiline
  • desethyloxybutynin
  • Carbachol
  • oxybutynin
  • Potassium
  • Animals
  • Butylamines (pharmacology)
  • Carbachol (pharmacology)
  • Guinea Pigs
  • In Vitro Techniques
  • Isometric Contraction (drug effects, physiology)
  • Male
  • Mandelic Acids (pharmacology)
  • Muscle, Smooth (drug effects, physiology)
  • Parasympatholytics (pharmacology)
  • Potassium (pharmacology)
  • Stereoisomerism
  • Structure-Activity Relationship
  • Urinary Bladder (drug effects, physiology)

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