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.