Constant-Rate Intravenous Infusion Methods for Estimating Steady-State Volumes of Distribution and Mean Residence Times in the Body for Drugs Undergoing Reversible Metabolism

Equations for the steady-state volumes of distribution (V_ss) and the mean residence times in the body (MRT) are derived for a drug and its metabolite subject to reversible metabolism and separately infused intravenously at a constant rate to steady state of both compounds. The V_ss and MRT parameters are functions of the integrals of plasma concentrations, plasma concentrations at steady state, and times to reach steady state of both drug and metabolite. In addition, the MRT values are functions of the infusion rates. These equations were validated by computer simulations and comparison with IV bolus dose parameters. These relationships extend the ability to assess the pharmacokinetics of linear reversible metabolic systems.