Determination of In Vivo Biotransformation Kinetics Using Early‐Time Biota Concentrations

Abstract

Technical challenges have hampered the characterization of biotransformation kinetics-a critical link in understanding and predicting the toxicokinetics and ecotoxicology of organic compounds. A shortcut approach to characterize the in vivo biotransformation rate constant (k M ) with incomplete pathway or metabolite details was proposed. The value of k M can be derived as ( ), with f PC (t) being the molar equivalent fraction of the parent compound (PC) at an early time t in both constant exposure and decay source chemical uptake scenarios. The approximation-based k M values agreed well with k M values derived from rigorous fitting or toxicokinetic modeling (n = 42, root mean square error = 0.30) with accuracy exceeding those of typical toxicokinetic or partitioning models. The method is accurate when sampling time is adequately resolved (i.e., t < ln(2)/k M ) but will likely produce biased k M values with improper time-averaging. The approximate equation yields consistent theoretical expectations for fast and slow biotransformation reactions and is fully compatible with standard bioaccumulation and toxicity testing protocols. The simplification strategy circumvents statistical complications and numerical issues inherent in regressing or modeling the toxicokinetics of multimetabolite systems and may be adapted to similar problems at other physiological scales or ecotoxicological contexts. The method can help advance interspecies comparison of chemical metabolism and support the development of in vitro-in vivo extrapolations and in silico models needed for building next-generation ecological and health risk-assessment practices.