The
indole-3-carboxylic acid scopoine
ester.
SDZ ICT 322, is a selective
hydroxytryptamine (5-HT3) antagonist, which after chronic treatment causes posterior subcapsular
cataracts and skin changes such as
hair loss, hyperaemia, desquamation and hyperkeratosis in rats. The detailed mechanisms underlying these changes are not yet known. In order to evaluate a possible oxidative stress-induced pathomechanism of
SDZ ICT 322, the antioxidative defence capacity in rats was modulated by feeding a special
vitamin E- and
selenium-deficient (VE/SeD) diet. For this purpose 32 male Wistar rats, age 4 weeks, were pretreated for 8 weeks with either a VE/SeD diet or a normal standard diet. Each dietary group was divided into 8 control and 8 SDZ ICT 322-treated animals.
SDZ ICT 322 was administered in feed to rats at an adjusted daily dose level of 125 mg/kg for 14 weeks. Plasma levels of
SDZ ICT 322 as well as of the N-desmethyl metabolite were similar in rats fed the different diets in weeks 3, 6 and 14. In
SDZ ICT 322 treated VE/SeD rats
cataracts were observed by week 7, whereas in rats fed normal diet
cataracts were first seen in week 14. In the normal dietary group no
corneal opacity was found after
SDZ ICT 322-treatment; however, a
corneal opacity was seen in the deficiency group in parallel with one of the
cataract animals in week 7. The incidence and severity of clinical skin signs were greater and their onset was earlier in the deficiency dietary group: onset occurred after 6 weeks compared to 9 weeks on the normal diet.
Thiobarbituric acid reactive substances, an
indicator mainly of oxidized
lipids, were statistically significantly increased in the urine of rats administered
SDZ ICT 322 and the VE/SeD diet.
Uric acid, which is an
endogenous antioxidant was statistically significantly decreased in the urine and plasma of
SDZ ICT 322 VE/SeD treated rats. The clinical eye and skin changes occurring early after VE/SeD feeding, the unchanged
drug plasma exposure and unchanged
drug metabolite formation in combination with the general pro-oxidative activity of the
drug suggest an oxidative stress-mediated pathomechanism of
SDZ ICT 322 at high dose levels in rats.