Species differences in the developmental toxicity of procymidone —Remarkable variation in pharmacokinetics, metabolism, and excretion—

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

“…In rats, hydroxylated-PCM-glucuronide is excreted into the bile, deconjugated to hydroxylated-PCM in the gastrointestinal tract, and reabsorbed, resulting in enterohepatic circulation and prolongation of its effect, whereas in rabbits and monkeys it is transferred to the bloodstream and then excreted rapidly in urine. 9 This key mechanism underlying the exposure of hydroxylated-PCM in humans was examined using chimeric mice with human hepatocytes. In the previous biliary excretion studies with rats, monkeys, and rabbits, the biliary excretion ratio (defined as the biliary excretion rate [% of dose] divided by urinary excretion rate [% of dose]) for hydroxylated-PCM-glucuronide was calculated as shown in Table 8.…”

“…9,11−15 In vitro receptor binding assay demonstrated that procymidone has antiandrogenic activity while PCM-CH 2 OH also has weak inhibitory activity. 12,13 In an in vivo experiment, 9 metabolism of procymidone in rats, rabbits, and monkeys was examined in detail. In the research, it was identified in rabbits and monkeys that hydroxylated-PCM is conjugated in liver, transferred to blood, and then rapidly excreted in urine, leaving the presence of only a low residual concentration of hydroxylated-PCM (Figure 2A).…”

An Investigation of the Metabolism and Excretion of KD101 and Its Interindividual Differences: A Microtracing Mass Balance Study in Humans

“…In contrast, glucuronide metabolites in rats would rather be excreted through the bile, followed by enterohepatic recirculation. To support this hypothesis, previous studies reported that glucuronide metabolites were excreted mainly in the bile in rats, but in the urine in humans 19,20 . Furthermore, the time for cumulative excretion through the main excretory route to reach plateau was much longer in rats (72 hours, feces) than in humans (24 hours, urine; Figure , Table ).…”

“…To support this hypothesis, previous studies reported that glucuronide metabolites were excreted mainly in the bile in rats, but in the urine in humans. 19,20 Furthermore, the time for cumulative excretion through the main excretory route to reach plateau was much longer in rats (72 hours, feces) than in humans (24 hours, urine; Figure 2, Table S1). This finding could also support our hypothesis.…”

Suspect screening and targeted analyses: Two complementary approaches to characterize human exposure to pesticides

“…Carboxylated-procymidone was found to be a major urinary endproduct in rats. On the contrary, hydroxylated-procymidone-glucuronide was a major component in rabbit and monkey urine, but only a minor component in rat urine (Tomigahara et al 2015). In our study, we mainly detected 1,2-dimethylcyclopropane-1,2-dicarboxylic acid (99%), whereas 3,5-dichloroaniline was rarely detected (only 10%), suggesting that urinary 1,2-dimethylcyclopropane-1,2-dicarboxylic acid, although undetected or only a minor metabolite in rodents (APVMA (Australian Pesticides and veterinary medicines authority) 2017; Shiba et al 1991;Tomigahara et al 2015) could be an appropriate candidate for monitoring procymidone exposure in humans.…”