Hepatic clearance with permeation and desorption
In vitro biotransformation assays are a promising tools for estimation of in vivo biotransformation kinetics. For extrapolation of biotransformation rate constants observed in vitro into corresponding in vivo biotransformation estimates, it is necessary to account not only for differences in nonspecific binding and amounts of biotransforming cells or proteins in vitro and in vivo, but also for limitations that occur in vivo but are not represented in the in vitro assays (in vitro-in vivo extrapolation, IVIVE). One example for such a limitation is blood flow limitation. Other limitations, which are commonly not considered in IVIVE, are slow permeation kinetics of the chemicals from blood into the biotransforming tissue and slow desorption kinetics of the chemicals from binding components of blood.
We developed a MS Excel calculation tool, that predicts in vivo hepatic clearances for fish from in vitro biotransformation rate constants considering these additional limitations. The predictions are directly compared with a prediction that considers blood flow limitation only enabling users to see whether slow permeation and slow desorption are relevant limitations in their scenarios of interest.
For additional details, we refer to the corresponding publication.
Krause, S. and K.-U. Goss, 2021, Relevance of desorption kinetics and permeability for in vitro-based predictions of hepatic clearance in fish. Aquatic Toxicology. 235: p. 105825.