The relationship between properties of antipsychotic drugs and cataract formation.
It has been reported that antipsychotic drugs such as phenothiazine derivatives, dibenzyl derivatives and others with calmodulin antagonism induce cataracts, which are generically called phenothiazine-induced cataracts. In the ophthalmologic field, the mechanism of cataractogenesis by such drugs is a problem urgently requiring a solution. This paper reports the relationship between the properties of such drugs and cataract formation. In this experiment, phenothiazine derivatives (chlorpromazine, trifluoperazine, prochlorperazine and perphenazine), dibenzyl derivatives (imipramine and amitriptyline), and other drugs (cyproheptadine and calmidazolium) were investigated. As a result, it was clarified that phenothiazine derivatives and calmidazolium have high lipophilicity, strong inhibition activity against phosphodiesterase, and a large permeability constant, and that those drugs induce high levels of Ca2+ accumulation in the lens. It was also revealed that those drugs were distributed only at the peripheral region of the lens after they had penetrated into the lens. From these findings, we inferred that the cataract formation may be caused by lens protein aggregation followed by the inactivation of calmodulin-dependent Ca-ATPase and subsequent Ca2+ accumulation in the lens. Furthermore, we have been convinced that it is necessary to lower at least the lipophilicity of these drugs to suppress the side effect of antipsychotic drugs inducing cataractic formation.
Kamei
A
A
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
Mizumoto
Y
Y
Takehana
M
M
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002386:Cataract / Q000139:chemically induced*; D004195:Disease Models, Animal; D007903:Lens Capsule, Crystalline / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques
D014150:Antipsychotic Agents; D002147:Calmodulin