Cataractogenesis in rats induced by in utero exposure to RG 12915, a 5-HT3 antagonist.
RG 12915, a selective 5-HT3 antagonist developed for the treatment of emesis and nausea associated with cancer chemotherapy, was administered by gavage to four groups of pregnant rats from Gestation Day 6 to 17 at doses of 0, 1, 10, and 100 mg/kg/day, as part of a Segment II (developmental toxicity) study. The 100 mg/kg/day dose was maternally toxic as indicated by decreased body weight gain and food consumption during the treatment period. A portion of the rats were allowed to deliver and rear their litters and three pups from two litters in the 100 mg/kg/day group were observed to have lens opacities (visible to the naked eye) at weaning. At a later examination, when the offspring were approximately 4 months old, four additional animals from the same two litters had cataracts. A slight growth retardation was also observed postweaning in the offspring of the 100 mg/kg/day group. To confirm the lens findings and more precisely define the no-effect dose, another study was conducted in which pregnant rats were administered daily RG 12915 doses of 0, 10, 30, 60, or 100 mg/kg/day from Gestation Day 6 to 17. There was a dose-related decrement in maternal body weight gain during the treatment period in the 30, 60, and 100 mg/kg/day groups (12, 28, and 47%, respectively) compared to the control group. A treatment-related incidence of nuclear cataract was observed in the offspring of the 60 and 100 mg/kg/day groups (litter incidence 6 and 45%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Lerman
S A
SA
Rhóne-Poulenc River Research and Development, Collegeville, Pennsylvania 19426-0107, USA.
Delongeas
J L
JL
Plard
J P
JP
Veneziale
R W
RW
Clark
R L
RL
Rubin
L
L
Sanders
J E
JE
D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000633:toxicity*; D002386:Cataract / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D007908:Lens, Crystalline / Q000473:pathology; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012702:Serotonin Antagonists / Q000633:toxicity*
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C065346:RG 12915