The determination of essential clearance, volume, and residence time parameters of recirculating metabolic systems: The reversible metabolism of methylprednisolone and methylprednisone in rabbits

Methods based on moment analysis are described which permit the calculation of the fundamental parameters of reversible drug/metabolite systems. These parameters include the four essential clearances of reversible and irreversible elimination, the central and steady-state distributional volumes, and the sojourn times or turnover rates of the metabolic pair. Additional parameters unique to interconversion systems are developed which describe the properties of metabolic entrapment ("recycled fraction"), conservation ("exposure enhancement"), and equilibrium resulting from reversible metabolism ("Percent parent drug at steady-state"). Parameters obtained by these methods are compared to those generated by conventional mammillary analysis. The influence of perturbation of essential parameters on the response of mammillary descriptors and the state of the interconversion system are simulated. The interconversion analysis is applied to disposition data for methylprednisolone and methylprednisone in the rabbit. Mammillary methods underestimate the metabolic clearance of these two steroids by 30%, while steroid turnover is underestimated by 100%. The steady-state volumes of distribution of the two steroids are overestimated by 10 and 61%. Additional literature data for disposition of several corticosteroids in various species and disease states are reanalyzed. Examination of cortisol/cortisone disposition in thyroid disorders reveals that mammillary methods detect the overall acceleration of steroid elimination in hyperthyroidism, but fail to reveal a 50% reduction in metabolite backconversion and decreased metabolic cycling. These moment analysis methods should facilitate characterization of the pharmacokinetics of the increasing array of reversible drug/metabolite systems.