Research ArticlesVolume of Distribution at Steady State for a Linear Pharmacokinetic System with Peripheral Elimination
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INTRODUCTION
The traditional equation for calculation of volume of distribution at steady state Vss from the time course of the total drug concentration in plasma after an intravenous (iv) bolus administration of dose, D, Vss = (D/AUC)*MRT has certain limitations: it is based on the assumption of drug elimination directly from plasma (or central compartment), where a drug was introduced. It also includes the assumption of an immediate equilibrium between bound and unbound drug fractions in plasma. The goal
EQUATION FOR THE STEADY-STATE VOLUME OF DISTRIBUTION WITH THE ACCOUNT OF PERIPHERAL ELIMINATION AND THE KINETICS OF THE WHOLE SYSTEM
Let us consider a linear pharmacokinetic system with drug input into the central compartment (plasma) and possible exit from any compartment. Such a system is characterized by a set of concentrations Ci = Ai/Vi, which correspond to different units of volumes Vi, where the drug is distributed, and containing the quantities of drug Ai. Vi is not necessarily the volume of the whole compartment (or body organ), but a volume of the phase with concentration Ci inside the compartment. For instance, it
EXPERIMENTAL DETERMINATION OF THE STEADY-STATE VOLUME OF DISTRIBUTION
A straightforward way to find Vss is to reach the steady state by subjecting the animal to a constant rate Ro iv drug infusion. The time required to reach the steady state, according to eq. 22, is determined by the smallest exponent λj, which is actually the terminal log-linear slope parameter β. During the interval of about five terminal half-lives (t1/2 = ln2/β), 97% level of the steady-state concentration values will be reached. After the analysis of plasma concentration Cp,ss and the total
DETERMINATION OF THE EXISTENCE OF PERIPHERAL ELIMINATION FROM PHARMACOKINETIC DATA
The time course of plasma concentration or the total quantity of drug in the body does not provide information about the exit routes of a drug. The calculated values of pharmacokinetic parameters are often interpreted as if the system eliminates a drug only from central compartment (plasma) eventually lumping together peripheral and plasma elimination. Let us consider, for instance, the system that exhibits both central and peripheral drug exit. The rate of plasma elimination, CluCu(t), is
CALCULATION OF THE PARTITION COEFFICIENT WITH THE ACCOUNT OF PERIPHERAL ELIMINATION
To calculate the steady-state volume of distribution from the physicochemical properties of drug and tissues using eq. 2, we need to obtain the plasma–tissue partition coefficient Pt-p for each organ.11,12 Let us consider a commonly used open mammillary model (Fig. 1), which considers the pharmacokinetic system as a central compartment (plasma) from which the drug can be eliminated or reversibly transferred to peripheral compartments, and each rate is the first order. The rate of possible
DISCUSSION
The obtained equation Vss = (D/AUC)*MRTint for determination of the steady-state volume of distribution from the time course of the total drug concentration in plasma after an iv bolus administration appears to be general for linear pharmacokinetics. It is based only on the assumption of linearity of the system and impulse drug input (as initial condition), and does not contain any special limitations on drug elimination routes and rates of possible reactions. The term MRTint cannot be
CONCLUSIONS
The equation for calculation of volume of distribution at steady state Vss with complete consideration of peripheral elimination and protein and tissue binding kinetics is obtained. Traditional equations for Vss = (D/AUC)*MRT and mean resident time MRT = AUMC/AUC are applicable only for the systems with central (plasma) elimination and an instant equilibrium between unbound and bound drug fractions in plasma. Experimental determination of Vss based on the obtained equations is considered. It is
REFERENCES (13)
- et al.
Noncompartmental determination of the steady-state volume of distribution
J Pharm Sci
(1979) - et al.
A priori prediction of the tissue:plasma partition coefficient of drugs to facilitate the use of physiologically based pharmacokinetic models in drug discovery
J Pharm Sci
(2000) - et al.
Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution
J Pharm Sci
(2002) - et al.
Theorems and implications of a model-independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. III. Peripheral bioavailability and distribution time concept applied to the evaluation of distribution kinetics
J Pharmacokinet Biopharm
(1987) Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data
J Pharmacokinet Biopharm
(1976)- et al.
Determination of common parameters of iodothyronine metabolism and distribution in man by noncompartmental analysis
J Clin Edocrinol Metab
(1975)
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