The Connection Between the Steady State (Vss) and Terminal (Vβ) Volumes of Distribution in Linear Pharmacokinetics and The General Proof That Vβ ≥ Vss

On the Accuracy of Estimation of Basic Pharmacokinetic Parameters by the Traditional Noncompartmental Equations and the Prediction of the Steady-State Volume of Distribution in Obese Patients Based Upon Data Derived from Normal Subjects

“…An observation of tissue-plasma partition coefficients being greater than their steady-state values after equilibration and consequently at terminal phase is in agreement with the general statement that V $ > V ss . 1 Hypothetically, the difference between the exactly calculated distribution volumes and the ones obtained by the commonly used equations can be large. For instance, if the parameters were taken as P l-p = 30, P f-p = 0.2, r = 0.55, V = 10 L, and Cl int f u /(rQ) = 5 (keeping the other parameters the same as used to generate Table 1), we would get the exact value of V ss as 74.3 L, whereas the common calculation by Eq.…”

“…In general, for a linear pharmacokinetic system, V $ ≥ V ss . 1 A substantial difference between V $ and V ss may indicate a relatively slow kinetics of drug transfer between plasma and peripheral tissues (organs) along with the slower elimination process, which, in turn, leads to a possible substantial delay in reaching the steady state in the body (or in certain organ) compared with plasma. 2 Both V ss and V $ are very complicated parameters determined by the physicochemical properties of the system.…”

“…4 for the terminal volumeof distribution. 1,7 An alternative method to obtain V ss is to calculate it based on the physicochemical properties of a drug, so that according to Eq. 1, it can be written as…”

“…The true value of t 1/2 may be much longer (by an order of magnitude) than that taken as t 1/2 ≈ ln2V ss /Cl because V $ can be much greater than V ss . 1 Formally, the assumption of central elimination embedded in the commonly used Eqs. 3 and 4 is rarely met.…”

The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

“…bolus administration, significant amounts of these drugs reach peripheral compartment during the initial distribution phase, and slow return to the central compartment limits the speed of drug elimination from the body during the elimination phase (Figures 1 and 3A). For such drugs, volume of distribution changes with time as a function of tissue penetration and binding of the drug [37,38]. In this case, the volume of distribution is initially low (V 1 --volume of the central compartment), increases to the higher value (V SS --steady-state volume) when the steady-state is achieved and reaches the maximum value (V b --terminal volume of distribution) during the elimination phase (linear terminal phase) ( Figure 3B and Table 2).…”