Mean Interconversion Times and Distribution Rate Parameters for Drugs Undergoing Reversible Metabolism

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Abstract
The mean interconversion time and recycling numbers are introduced as intrinsic metabolic interconversion and distribution parameters for drugs undergoing linear reversible metabolism. Equations for these parameters, the distribution clearance, and the mean transit time in the central and peripheral compartments are derived for a metabolic pair where interconversion and elimination occur in central compartments. These parameters can be calculated from plasma concentration versus time slopes and intercepts, AUC, and AUMC data of parent drug and its metabolite partner following iv administration of each compound. The mean time analysis is illustrated with disposition data obtained previously for methylprednisolone and methylprednisone in the rabbit. Examination of mean times and additional properties of the system reveals that total exposure time of methylprednisolone is weakly influenced by the metabolic interconversion process, whereas the total exposure time of methylprednisone is strongly influenced by the process. In addition, the tissue distribution processes moderately influence the total exposure times of both compounds. The derived mean time parameters, along with previously evolved equations for clearances, volumes of distribution, moments, and mean residence times allow comprehensive analysis of linear, multicompartmental reversible metabolic systems.