Species differences in the developmental toxicity of procymidone—Placental transfer of procymidone in pregnant rats, rabbits, and monkeys—

Abstract

To clarify species differences in the developmental toxicity of procymidone (Sumilex ® , a fungicide for agricultural use), placental transfer studies were conducted using 14 C-labeled procymidone in pregnant rats, rabbits, and monkeys. These studies demonstrated that maternal-to-fetal transfer of the parent compound and its hydroxylated metabolite, which are both weak anti-androgenic agents, occurred more easily than that of other metabolites, with much higher absolute concentrations achieved in the fetal circulation of rats than of rabbits or monkeys. Notably, in rats, the fetal plasma concentration of the hydroxylated metabolite was higher than that of procymidone, especially after repeated oral administration of procymidone. These results suggest that the hydroxylated metabolite is the most relevant metabolite involved in teratogenic activity in rats.

Identification of Metabolism and Excretion Differences of Procymidone between Rats and Humans Using Chimeric Mice: Implications for Differential Developmental Toxicity

“…Pharmacokinetics, Metabolism, and Excretion Studies (Groups 1−4). After the quarantine period of over 2 days, 14 C-procymidone in corn oil was administered as the single oral dose at 37.5 mg/kg/10 mL (Groups 1 and 2, low dose) or 62.5 mg/kg/10 mL (Groups 3 and 4, high dose). The low dose (37.5 mg/kg) was the lowest toxicologically effective dose to present the developmental toxicity as confirmed in our laboratory and the high dose (62.5 mg/kg) was the toxicological effect level showing decreased spontaneous activity.…”

“…The mice were anesthetized (by intraperitoneal administration of a mixture of xylazine hydrochloride and ketamine hydrochloride) and gall bladders were cannulated with polyethylene tubes. After recovery from anesthesia, 14 C-procymidone was orally administered at 37.5 mg/kg to each mouse.…”

“…4,7 Calculations. The amount of 14 C was calculated from the weight of solution administered to each mouse. The maximal radioactivity and time to reach maximal radioactivity were used as values for the maximal concentration in plasma (C max ) and the time to reach C max (T max ).…”

“…On the other hand, the kinetics of hydroxylated-PCM was identified to be different in rats, and the glucuronide is excreted in bile and deconjugated to hydroxylated-PCM in the gastrointestinal tract and reabsorbed, resulting in recycling through the enterohepatic circulation and increased exposure in rats (Figure 2B). In another in vivo experiment, 14 PCM and hydroxylated-PCM were transferred to the fetus in rats, rabbits, and monkeys, but the amounts were no less than 6 times higher in rats than in rabbits and monkeys. Further, rat fetuses tended to accumulate hydroxylated-PCM upon repeated oral administration of procymidone.…”

Researches on the evaluation of pesticide safety in humans using a pharmacokinetic approach

“…3) The species difference in the maternal exposure to the hydroxylated metabolite results in a significant difference in fetal exposure. 4) From these results, it was suggested that the species difference in the developmental toxicity of procymidone is mainly due to variation in the level of exposure to the causal substance, hydroxylated metabolite, and this variation stems from interspecies differences in the biliary excretion route of the glucuronide. To assess the teratogenic risk associated with procymidone in humans, the excretion route and rate of formation of glucuronides, which are key factors involved in the mechanism of the toxicity must be clarified.…”