Real and apparent volumes of distribution

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Lugar: Basignstoke; Año: 2022; p. 1043 - 1051

The real volume of distribution of a drug has physiological meaning, as it is related to the volume of body water accessible to the drug (including intracellular and extracellular fluid). Total body water represents 50% to 70% of the total body weight; two thirds of it correspond to intracellular fluid, whereas the remaining one third corresponds to extracellular fluid (75% interstitial fluid and 25% plasma) [1]. Since an adult presents about 600 mL of body water per kilogram of body weight (which varies between 500 and 700 mL/kg depending on sex and age), the upper bound for the real volume of distribution of a drug will be around 42 L for a person weighting 70 kg. No drug might have, for such an individual, a real volume of distribution significantly above that approximate value. Furthermore, only a drug that can access all body volumes (plasma volume plus interstitial and intracellular fluids) would achieve the upper bound of the real volume of distribution. Conversely (i.e. if drug does not fully distribute to a given tissue or organ), the real volume of distribution will be below the correspondent upper limit. After achieving systemic bioavailability, drug molecules will almost instantaneously disperse within the plasma pool. Accordingly, the lower bound of the real volume of distribution would be the plasma volume, corresponding to a drug that can neither extravasate nor penetrate blood cells. Note that, as happens with other reference body volumes, plasma volume is also subjected to significant variation across sex, age, body surface area or disease states. For instance, male adults between 60 and 65 kg show plasma volumes close to 3,000 mL (mean plasma volume between 46.1 and 51.5 mL/kg, depending on the age group) [2]. The mean plasma volume per kilogram of body weight tends to be smaller in female adults [3, 4], while a considerable plasma volume expansion (volume excess) has been observed in patients with chronic heart failure [5]. In contrast, apparent volumes of distribution are proportionality constants between the total amount of drug in the body and plasma concentrations [6], arising from classic compartmental pharmacokinetic models. A compartment model is a handy mathematical construct that allows a relatively simple description of the behavior of a drug substance when administered to a subject. In the framework of classic compartmental models, a compartment is a mathematical (abstract or imaginary) concept that describes a space in the body that the drug appears to occupy. Compartmental models might comprise different number of compartments (the one-compartment model being obviously the simplest and the least accurate one). This kind of models assume that once it enters one compartment, the drug instantaneously and homogeneously distributes across the compartment. Movement between compartments, however, is not an instantaneous but a linear (i.e. first order kinetics) time-dependent process. This is of course a convenient oversimplification with no direct basis in reality. The apparent volume of distribution Vd, in the context of the one-compartment model, is calculated as follows:A/C_p =V_d (1)where A represents the total amount of drug in the body at a given time t and Cp denotes the total drug concentration in plasma at that same time (note that total drug concentration comprises both bound and unbound drug). As in the one-compartment model distribution is assumed to be instantaneous in the single compartment under consideration, the ratio between A and Cp (in other words, Vd) will be constant (that is, time-independent). In the two-compartment pharmacokinetic model, in contrast, several Vd are to be considered since the proportionality ratio between A and Cp will assume different values depending on the phase of drug disposition (e.g. just after drug injection, once distribution has been completed or after that, in the terminal phase of the time-concentration curve). Although the value of Vd is often used to draw conclusions about drug distribution, this parameter was not initially conceived to evaluate distribution in the different physiological spaces [6]. It only provides a reference for the plasma concentration anticipated for a given dose, but it gives little information concerning the specific pattern of distribution. However, as explained in the next section, some physiological meaning may be drawn from the apparent distribution volumes in the light of plasma- and tissue-binding equilibria. Furthermore, whereas two- and three-compartment models have found more general applications, there are some drug classes for which pharmacokinetics are reasonably well predicted by the one-compartment model. Particularly, highly hydrophilic drugs confined to body water. For instance, the first method used to fit serum concentrations of aminoglycoside antibiotics to individual patient models was the Sawchuk-Zaske approach, which used linear regression analysis and assumed a one-compartment model [7].