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.
Smith
E R
ER
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, USA.
Wright
S E
SE
Aberg
G
G
Fang
Y
Y
McCullough
J R
JR
D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
D002082:Butylamines; D008333:Mandelic Acids; D010276:Parasympatholytics; C010637:terodiline; C032681:desethyloxybutynin; D002217:Carbachol; C005419:oxybutynin; D011188:Potassium