Abstract
Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.
Highlights
Despite their primary role in estimating pharmacokinetic parameters that can be used to design optimum dosing regimens to achieve plasma drug concentrations within therapeutic range, it is generally believed that the apparent volume of distribution cannot be estimated in multi-compartment models and that the compartment volumes of multi-compartment pharmacokinetic models bear no physiological significance
We have produced the real-time explicit solutions to drug concentration for multiple IV boluses and multiple oral doses in a two-compartment model and utilized them along with the analytical solutions of the multiple intermittent infusions that we have reported elsewhere to analyze published clinical data of prazosin
The particular solutions and real-time series equations to drug concentration after multiple intermittent constant rate constant dosing frequency infusions that we have recently developed have allowed us to construct the infusion and elimination phases of plasma or central compartment prazosin concentration as a function of infusion dose number and total time using Equation (76) and Equation (77), respectively, in an open two-compartment model
Summary
Despite their primary role in estimating pharmacokinetic parameters that can be used to design optimum dosing regimens to achieve plasma drug concentrations within therapeutic range, it is generally believed that the apparent volume of distribution cannot be estimated in multi-compartment models and that the compartment volumes of multi-compartment pharmacokinetic models bear no physiological significance. This is no longer true [1] [2] [3]. The value of the Vd of a substance is dependent on the actual phase volumes, and at constant phase volumes, phase solute concentrations are directly proportional to the total mass of the solute xs in the system as shown by Equation (2), below: Vd=,1 xs x1
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