ABSTRACT
This chapter describes the biochemical and physiological considerations required for accurate extrapolation of in vitro biotransformation kinetics to whole organisms for implementation in physiologically-based pharmacokinetic models. In order for these extrapolations to be meaningful, the in vitro experiments must be done under the appropriate conditions to accurately determine the kinetic parameters of the metabolic reactions being studied. Chemical metabolism can be studied in the whole animal—research species or human—or can be studied under carefully controlled conditions in vitro in the laboratory. Competitive inhibition by alternative substrates deserves special consideration in toxicology studies, where insoluble toxicants are often delivered to in vitro or in vivo systems in carrier solvents. The enzymes involved in biotransformation can be studied in vitro using isolated perfused organs, intact cells, subcellular fractions, or purified proteins. Freshly isolated hepatocytes in vitro have long been known to qualitatively model xenobiotic biotransformation in vivo in that the same array of metabolites is formed.
