Volumes of distribution

Generally, the concentration of mAbs in the interstitial fluid is rather small, with reported serum tissue ratios in biopsy samples ranging from 2 to 10. However, as this sampling technique normally uses homogenization during preparation, only a mixed concentration across all different cell types and fluids of the entire tissue is provided, and the ratios will most likely be an overestimation of the real situation. 

Generally, the estimated volumes of distribution are small and relatively homogeneous (Table 3.5). mAbs initially distribute into a restricted central volume (Vc) of 3-5 L, which in humans approximates the serum volume. In order to evaluate the value in patients with respect to physiology, it must be kept in mind that, especially in tumor patients, the cellular fraction in blood and the hematocrit may be decreased and hence the serum volume will be increased. 

With the development of special types of mAbs such as monoclonal intrabodies, antibody fragments with considerably lower molecular mass (see Section 3.4.2.5), enhanced tissue penetration is expected. Studies conducted in vitro or in animals revealed that small-sized antibody fragments can penetrate tissues more easily, might potentially cross the blood-brain barrier, and can be delivered locally to the 

Monoclonal antibody Volume of distribution (Vss) [L] Clearance (CL) [mL/h] Half-life (tn/2) [days] 

The volume of distribution (VD) for a drug is the apparent volume that accounts for the total dose administration based on the observed plasma concentration. The plasma volume of the average adult is approximately 3 L. Therefore, an apparent volume of distribution larger than the plasma compartment (i.e. greater than 3 L) indicates that the drug is also present in tissue or fluid outside the plasma compartment. The volume of distribution represents a complex combination of multiple chemical and biochemical phenomena. Nevertheless, in general terms and considering only the passive distribution processes, the distribution of a compound in the body depends on the partition of the compound between the differ- 

There are different families of enzymes involved in the xenobiotic metabolism, but the most relevant one in drug discovery is the cytochrome P450 (CYP) family. The major CYP enzymes contributing to drug metabolism are  

The percentage of drugs designated to be metabolized by each CYP is obtained from historical data [36]. In the future other CYPs may increase in relevance for new chemical entities. 

The interaction between a substrate and a cytochrome can be described in the same way as the interaction of a compound with any pharmacological target. The crystal structures of several enzymes are published in the protein data bank (pdb)  

The inhibition of several cytochrome enzymes has been studied using different MIF-based techniques. One of the experimental factors that has to be considered in the modeling of this property is the type of inhibition. Therefore, it is relevant to study a homologous series of compounds which, hypothetically, has the same inhibition type, or it has to be experimentally checked. 

The half-life (fi/2) of a drug is a function of two variables clearance and volume of distribution. Half-life is directly related to volume of distribution (VD) and inversely related to clearance (CL)  

while the half-life can be lengthened by reducing the clearance (as stated above), the half-life can also be lengthened by increasing the VD. 

To understand VD at its most basic element, begin by considering a vessel with no volume markings on it that contains an unknown volume of solvent. Into this volume of solvent is dissolved a known mass of solute. Then, a sample of the solution is removed and the concentration of the solute is measured. By knowing the mass of solute added and subsequently measuring the concentration of the solution, the volume of the solvent can be computed  

To add a bit of complexity, now imagine that an unknown portion of this solute sticks to the inside walls of the vessel, and that the extent of this is not known. When this occurs, the measured concentration of a sample of the solution will be lower. When this lower measured concentration is combined with the known mass of solute that was dissolved, the calculation of the volume of the solvent will yield an overestimate. This is analogous to a drug that leaves the plasma and enters tissues - the calculated volume will increase. 

Unlike the simple example of the solution described above, a human body is a complex mixture of components (tissues, proteins, membranes, etc.). Yet, in human pharmacokinetic studies, with rare exceptions only the plasma 

Poulin and Theil have developed a mechanistic model for estimating the Vd based on physiologically based pharmacokinetics (PBPK). For this method, the tissue plasma partition coefficient for each organ of the body is calculated by consideration of the volume fraction of neutral and phospholipids and water found in the tissues of a particular organ. For example, the volume fraction of neutral lipids in human adipose tissue is 0.79 whereas the volume fraction of neutral lipids in cardiac tissue is 0.0115. By contrast the volume fraction of water in adipose and heart are 0.18 and 0.76 respectively. Combined with the P, these volume fractions are used to estimate the distribution of a drag molecule into each tissue. Summation of the product of tissue volume and tissue/plasma partition coefficient produces the estimate of Vd.  

One of the earliest attempts to model chemical transformations in a living system was carried out in 1987. This system consists of a biotransformation database and one or more logic-based prediction tools.This system and other knowledge-based systems provide a branching tree of possible metabolites but provide no information on likelihood or quantitative rates of production. 

Structure-based molecular modeling is another promising approach to improvement of the prediction of region-specificity of P450 metabolism. De Groot developed pharmacophore models and three-dimensional quantitative structure-activity relationships either alone or in combination with protein homology models to provide substrate-binding specificity information for CYP jgS.  

Most recently, in silico methods have been apphed to the systems biology of metabolic pathways. An analysis of the human genome assigns 2709 human enzymes to 896 bioreactions 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at http //HumanCyc.org/. 

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Factor Synthesis site Biologica I half-life, h Volume of distribution, MPV" Hemostasis concentratio 0/ n, % Per population Inheritanc d e pattern Chromoso me... 

Theoretical volume of distribution (Vj) of a chemical is the volume in which the chemical would be distributed if its concentration were equal to a theoretical steady-state plasma concentration (Cq) at time zero. The volume of distribution is thus obtained quite similarly as the steady state concentration of a compound in the workroom air ... 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Variance ratio, 239 Venn diagram, 177, 192f Viral coat protein, 44, 53 Volume of distribution, 165, 168... 

The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 min on Day 1 of each 21-day cycle. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70-90% of the dose recovered unchanged within the first 24 h following administration. Pemetrexed has a steady-state volume of distribution of 16.1 L. Pemetrexed is highly bound (approximately 81%) to plasma proteins. Binding is not affected by the degree of renal impairment. Plasma... 

One solution to the volume problem was proposed using moment analysis. The steady-state volume of distribution (Vss) can be derived from the area under the curve (AUC) and the area under the first moment curve (AUMC). 

The apparent volume of distribution (Vd) slightly increases depending on plasma volume (Fp), tissue volume (Ft), and free tissue fraction (ft) whereas the half-life slightly decreases with significantly increasing free plasma fraction. 

Figure 15.5 Sammon map with SVM classification of drugs based on their volume of distribution (a) and plasma half-life (b) [95].

Lombardo F, Obach RS, Shalaeva MY and Gao F. Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem 2002 45 2867-76. 

Lobell M and Sivarajah V. In silico prediction of aqueous solubility, human plasma protein binding and volume of distribution of compounds from calculated pKa and AlogP98 values. Mol Divers 2003 7 69-87. 

Estimation of Volume of Distribution from Physical Chemistry... 

The distribution of a drug in the body is largely driven by its physicochemical properties and in part for some compounds by the contribution of transporter proteins [17]. By using the Oie-Tozer equation and estimates for ionization (pfCj). plasma protein binding (PPB) and lipophilicity (log quite robust predictions for the volume of distribution at steady state (Vdss), often within 2-fold of the observed value, can be made [18]. 

Van de Waterbeemd, H. Which in vitro screens guide the prediction of oral absorption and volume of distribution Basic Clin. Pharmacol. Toxicol. 2005, 96, 152-165. 

M. Y., Gao, F. Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics. J. Med. Chem. 2004, 47,1242-1250. 

Aqueous solubility is not usually considered a priori as a problem in the drug discovery of acidic compounds. More important issues are (i) the high serum albumin binding of stronger acids, (ii) the very low or nonexistent central nervous system penetration of stronger acids, (iii) the low volumes of distribution of acids limiting these mostly to plasma compartment targets, (iv) the possibility of formation of... 

Hollosy, F., Valko, K., Hersey, A., Nunhuck, S., Keri, G., Bevan, C. Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning. J. Med. Chem. 2006, 49, 6958-6971. 

The AUC is a measure of bioavailability, i.e. the amount of substance in the central compartment that is available to the organism. It takes a maximal value under intravenous administration, and is usually less after oral administration or parenteral injection (such as under the skin or in muscle). In the latter cases, losses occur in the gut and at the injection sites. The definition also shows that for a constant dose D, the area under the curve varies inversely with the rate of elimination kp and with the volume of distribution V. Figure 39.6 illustrates schematically the different cases that can be obtained by varying the volume of distribution Vp and the rate of elimination k both on linear and semilogarithmic diagrams. These diagrams show that the slope (time course) of the curves are governed by the rate of elimination and that elevation (amplitude) of the curve is determined by the volume of distribution. 

Fig. 39.6. (a) Time courses of plasma concentration Cp in the one-compartment open model for intravenous injection, with different contingencies for the transfer constant of elimination kfe and the volume of distribution Vp. (b) Time courses of plasma concentration Cp as in panel (a) on semilogarithmic plots. 

Clearance is defined as the fraction of the volume of distribution Vp that is cleared of the drug per unit of time. In the case of elimination from the kidneys, the clearance provides a measure for the effectiveness of renal elimination with respect to the dmg under study. 

Plasma volume of distribution Area under the curve ... 

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