Distribution apparent volume

Distribution - Binding to plasma proteins is low (10% to 33%), and the apparent distribution volume at steady state with IV administration has been reported to be approximately 6 L/kg. 

Pharmacokinetics provides the scientific basis of dose selection, and the process of dose regimen design can be used to illustrate with a single-compartment model the basic concepts of apparent distribution volume (Vd), elimination half-life (b/2) and elimination clearance (CLg). A schematic diagram of this model is shown in Figure 2.4, along with the two primary pharmacokinetic parameters of distribution volume and elimination clearance that characterize it. 

FIGURE 2.4 Diagram of a single-compartment model in which the primary kinetic parameters are the apparent distribution volume of the compartment (V ) and the elimination clearance (CLg). 

Initiation of Drug Therapy (Concept of Apparent Distribution Volume)... 

In this case, the apparent distribution volume of 536 L is much larger than is anatomically possible. This apparent anomaly occurs because digoxin has a much higher binding affinity for tissues than for plasma and the apparent distribution volume is the volume of plasma that would be required to provide the observed dilution of the loading dose. Despite this apparent anomaly the concept of distribution volume is clinically useful because it defines the relationship between plasma concentration and the total amount of drug in the body. Further complexity arises from the fact that only one of three different distribution... 

FIGURE 2.5 Siimilation of plasma (solid line) and tissue (heavy dashed line) digoxin concentrations after intravenous administration of a 0.75-mg loading dose to a 70-kg patient with normal renal function. Cq is estimated by back extrapolation (dotted line) of elimination-phase plasma concentrations. is calculated by dividing the administered drug dose by this estimate of Cq, as shown. Tissue concentrations are referenced to the apparent distribution volume of a peripheral compartment that represents tissue distribution. (Reproduced with permission from Atkinson AJ Jr, Kushner W. Annu Rev Pharmacol Toxicol 1979 19 105-27.)... 

Many drugs have distribution volumes that exceed expected values for TBW, or are considerably larger than ECF despite extensive binding to plasma proteins. The extensive tissue binding of these drugs increases the apparent distribution volume that is calculated by reference to drug concentrations measured in plasma water. By modifying Equation 3.1 as follows. 

The result of this calculation, the distribution volume, in fact only rarely corresponds with a physiological body space such as extracellular water or total body water, for it is a measure of the volume a drug would apparently occupy knowing the dose given and the plasma concentration achieved and assuming the entire volume is at that concentration. For this reason, it is often referred to as the apparent distribution volume. Indeed, for some drugs that bind extensively to extravascular tissues, the apparent distribution volume, which is based on the resulting low plasma concentration, is many times total body volume. 

The list in Table 7.2 illustrates a range of apparent distribution volumes. The names of those substances that distribute within (and have been used to measure) physiological spaces are printed in italics. 

Pharmacokinetics. Amiodarone is effective given orally its enormous apparent distribution volume (701/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t) of 54 days after multiple dosing signifies slow release from these sites (and slow accumulation to steady state means that a loading dose is necessary, see Table 24.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts. 

Photosensitized polymerization of lens proteins can be selected as a measure of eye phototoxicity (Chapter 11). Proteins isolated from calf lens are suitable to simulate the conditions in the human eye. The reaction mechanisms can be evaluated by adding various quenchers to the reaction medium during irradiation. Chloroquine, hydroxychloroquine, mefloquine, and quinacrine induced polymerization under the given experimental conditions (Kristensen et al., 1995). These compounds have a large apparent distribution volume and a long elimination half-life and must therefore be considered as potential photosensitizers in the eye. Primaquine and quinine were also shown to induce polymerization of lens proteins in vitro but are less likely to reach the eye in vivo due to fast elimination from the body. 

For the antimalarial drugs, however, essential data are available in the literature. Many of the antimalarials investigated have a large apparent distribution volume (Vd) and a long elimination half-life (t1/2) (Table 10.1). This reflects accumulation of the drugs in body tissues. Most of the adverse effects associated with the use of antimalarials are related to the eye and skin. The retina is richly supplied with blood vessels, but the blood-retinal barrier is normally very tight and therefore restricts... 

The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Within 3 minutes, 80% response will be reached, with the peak effect occurring at 6 to 10 minutes. Pharmacokinetics After IV administration, flumazenil has an initial distribution half-life of 7 to 15 minutes and a terminal half-life of 41 to 79 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. After redistribution the apparent volume of distribution ranges from 0.77 to 1.6 L/kg. Protein binding is approximately 50%. 

The serum half-life averaged 1.7 hours in subjects with normal renal function. In healthy subjects, the serum clearance was 91 mL/min and renal clearance was 56 mL/min the apparent mean volume of distribution at steady state averaged 12.6 L. 

Absorption/Distribution - Following oral administration, stavudine is rapidly absorbed with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Binding to serum proteins was negligible. Oral bioavailability in adults is approximately 86%. The apparent oral volume of distribution is about 66 L. 

A Apparent Volume of Distribution Volume of distribution (Vd) is a proportionality factor that relates the amount of a drug in the body to its blood or plasma concentrations,... 

Volume of distribution (Vd) The volume of body fluid in which a xenobiotic is apparently distributed when administered to an animal. 

Figure 58. Effect of Moisture on Heat Conductivity, Apparent Specific Volume, and Diffusivity of Quartz Whose Size-Distribution Is Given in Table 37.

In swine, following intra-aortic administration, the disappearance of parent T-2 toxin followed a two compartment open model with mean elimination phase half-life of 13.8 min and mean apparent specific volume of distribution of0.3661/kg (Beasley et al, 1986). Parent T-2 toxin was not detected in plasma, urine, or liver but was transiently present in lymphoid tissues. T-2 toxin and metabolites were eliminated as glucuronide conjugates into bde, undergoing deconjugation in the intestinal tract by microbial action and then underwent enterohepatic recirculation (Corley et al, 1985). 

Figure 1 Apparent pore volume distributions of particulate silicas Gl-G to G5-G according to BJH from the nitrogen desorption isotherms.

The sum of Vi and V2 is termed the apparent volume of distribution at steady state (Vrf(ss)) and is the third distribution volume that we have described. Note also that CLi = k2iVi = ki2V2-... 

The distribution volume of M8 (v3) was hxed to 1L and the estimated parameter was an apparent metabolic clearance of nelhnavir to M8. 

Altered tissue binding may also affect the apparent volume of distribution of a drug. For example, the distribution volume of digoxin has been reported to be reduced by 30% to 50% from normal values in patients with renal disease. It has been postulated that this reduction in the distribution volume is secondary to a decrease in tissue... 

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