Species differences in the developmental toxicity of procymidone

—Remarkable variation in pharmacokinetics, metabolism, and excretion—

Abstract

There are species differences regarding the developmental toxicity of procymidone (Sumilex®), a fungicide with a weak anti-androgenic activity. To clarify key factors of these species differences, pharmacokinetic and excretion studies in rats, rabbits, and monkeys were conducted using ¹⁴C-labeled procymidone. One hydroxylated metabolite of procymidone (Hydroxylated-PCM: very weak anti-androgen) was found to exist longer and at a much higher concentration in rat plasma than in rabbit and monkey plasma. In rabbits and monkeys, Hydroxylated-PCM was transformed into a glucuronic acid conjugate (Hydroxylated-PCM-glucuronide: non-anti-androgen) and rapidly excreted into urine as a major metabolite. On the other hand, it was a minor metabolite in rat urine. The results of biliary excretion studies indicated that these species differences were caused by the species differences in the biliary excretion of Hydroxylated-PCM-glucuronide; this variation in biliary excretion rate was concluded to be related to species differences in developmental toxicity.