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Toxicological Sciences 66, 166-172 (2002)
Copyright © 2002 by the Society of Toxicology

SAFETY EVALUATION

Muscarinic Receptor Antagonist-Induced Lenticular Opacity in Rats

Geneviève Durand*, Marie-Françoise Hubert*, Hiroshi Kuno{dagger}, William O. Cook{ddagger}, Christine Boussiquet-Leroux*, Roger Owen*, Yukio Fujimaki{dagger}, Masayuki Kemi{dagger}, Michel Virat* and Matthew J. van Zwieten{ddagger}

* Laboratoires Merck Sharp and Dohme-Chibret, Route de Marsat, Riom, 63963 Clermont-Ferrand Cedex 9, France; {dagger} Banyu Development Research Laboratories, Menuma, Japan; and {ddagger} Merck Research Laboratories, West Point, Pennsylvania

Investigations on compound A, an M2-sparing M3 muscarinic receptor antagonist, showed that focal polar anterior subcapsular lenticular opacities, characterized by focal epithelial proliferation, developed in Sprague-Dawley rats. The incidence and bilateral localization of this change increased generally with dose and time, though plateauing after 8 months of treatment; however the severity progressed very slightly. Over a 1-year period, no anterior cortical lens fiber changes or other histological ocular changes developed. A decreased severity of the change and apoptosis suggested some regression after a 26-week recovery period. Two nonselective muscarinic receptor antagonists, atropine and tolterodine, induced similar lenticular changes in rats. A hypothesis in relation to an indirect effect of the drug, such as increased illumination of the lens due to mydriasis observed with all these compounds, was investigated and disproven. Because these opacities are induced by structurally unrelated muscarinic receptor antagonists (atropine and tolterodine), it is likely that these lenticular changes are the result of muscarinic receptor inhibition. However, hypotheses regarding a direct effect of the drug on muscarinic receptors in the lens epithelium, possibly mediated by drug and/or metabolite(s) in the aqueous humor and/or lens epithelium, remain to be investigated. This lenticular opacity is similar to that observed spontaneously in Sprague-Dawley rats, although the latter occur at a lower incidence. No such lenticular opacities have been reported in other animal species, including man, after treatment with muscarinic receptor antagonists.

Key Words: selective and nonselective muscarinic receptor antagonists; lens; epithelial proliferation; dose-related response; rat.


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