Prediction of human pharmacokinetics of procymidone and its major phase I and II metabolites using a PBPK model with enterohepatic circulation

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is a valuable approach for addressing the scarcity of human toxicokinetic data, particularly in the risk assessment of agrochemicals. While numerous PBPK models have been developed to describe various pharmacokinetics processes, modeling the complex kinetics of enterohepatic circulation remains challenging. Procymidone, a widely used fungicide, undergoes initial metabolism to hydroxylated-procymidone, an active metabolite with antiandrogenic properties, followed by glucuronidation. In rabbits, monkeys, and chimeric mice with humanized liver, the glucuronic acid conjugate is rapidly excreted in urine. However, in rats, it is primarily excreted into bile, deconjugated in the gastrointestinal tract, and subsequently reabsorbed, leading to enterohepatic circulation. This species difference in biliary excretion is considered a key factor contributing to the elevated plasma levels of hydroxylated-procymidone in rats, which are associated with rat-specific developmental toxicity. To estimate human internal exposure to hydroxylated-procymidone, a PBPK model was developed incorporating quantitative prediction of complex pharmacokinetics. This model was constructed without relying on human in vivo data, instead integrating advanced in vitro systems, such as bile canalicular membrane transporter assays using sandwich-cultured human hepatocytes and in vitro-to-in vivo extrapolation. By comparing the predicted plasma concentration of hydroxylated-procymidone in humans with measured values in rats, significant interspecies differences were observed, suggesting that the risk of developmental toxicity associated with procymidone exposure is lower in humans than in rats.