Domain of validity of classical models of leucine metabolism assessed by compartmental modeling

Whole-body modeling of in vivo leucine (an essential amino acid) metabolism is fundamentally difficult due to the complexity of the system. This has favored the use of two simple kinetic models, the so-called primary and reciprocal pool models, to interpret tracer data, but their domain of validity is uncertain. We define here the error of these two approaches by using comprehensive compartmental models of leucine metabolism as true representations of the leucine system. Of particular interest is the comparison of the two simple models with an 11-compartment model characterized by a rich intracellular compartmentation that has recently been proposed as a sound physiological description of the system. Formulas are derived that define in structural terms the error of the primary and reciprocal pool models.