Rat-to-human PBPK model of U-47700: Unveiling pharmacokinetic risks of a synthetic opioid through interspecies extrapolation.

U-47700, a synthetic μ-opioid receptor agonist and emerging new psychoactive substance, poses critical public health risks due to its high abuse liability and fatal overdose potential. Ethical barriers prohibit clinical pharmacokinetic studies of such controlled substances, necessitating alternative approaches. Here, we developed the first physiologically based pharmacokinetic (PBPK) model for U-47700 by integrating in vitro experiments-including Caco-2 permeability, tissue-plasma partitioning, plasma protein binding, and human liver microsomal clearance. The rat PBPK model accurately predicted plasma concentration-time profiles across doses, and the metabolite's PBPK model was further established and validated to describe the kinetics of N-desmethyl-U-47700 and N,N-didesmethyl-U-47700. Human extrapolation via IVIVE (in vitro-in vivo extrapolation) and allometric scaling revealed rapid systemic clearance (0.944-1.371 L/h/kg). For illicit drugs like U-47700, where clinical trials are unfeasible, this PBPK framework bridges computational modeling, preclinical insights, and real-world evidence, offering a critical tool to decode pharmacokinetic curves, estimate administration timelines from postmortem samples, and assess polydrug interaction risks. By enabling mechanistic insights into synthetic opioid toxicity, this work informs overdose prevention strategies and mitigates the societal impact of high-risk designer drugs.