Distribution volume, parameter

Usually, one has obtained an estimate for the elimination constant and the distribution volume Vp from a single intravenous injection. These pharmacokinetic parameters, together with the interval between administrations 0 and the single-dose D, then allow us to compute the steady-state peak and trough values. The criterion for an optimal dose regimen depends on the minimum therapeutic concentration (which must be exceeded by and on the maximum safe... 

The term refers to the distribution volume of the effect compartment and thus the effect compartment becomes S5monymous with the central compartment. The above equation contains three unknown parameters making it impossible to predict the concentration or the effect (E(t)) as a function of time if we define the ratio of concentration in the effect compartment and the central compartment, or the partition coefficient, at equilibrium. 

The three main parameters of clinical pharmacokinetics are clearance, distribution volume, and bioavailability. Clearance is the rate at which the body eliminates a drug. In order to achieve a steady-state concentration, the drug must be given so that the rate of clearance equals the rate of administration. If the drug is given as quickly as it is eliminated, a consistent level in the body will be maintained. 

Fig. 4. Backfolding in dendrimers as predicted by analytical theory [12]. Free end probability distribution function of the radial distance for generations 2-7. All data has been calculated assuming a realistic excluded volume parameter of the segments of the dendrimer (see [12] for further details). Reproduced with permission from [12]...

Half-life is a composite parameter depending on the efficiency of drug elimination (Cl) and its distribution volume (VD). For a one-compartment system. 

Calculations of the variations expected in the fluorescent-yield (FY) profiles as a function of the distribution model parameters are shown in Figure 7.19. When the species of interest resides predominantly at the solid surface, the FY profile shows a maximum at the critical angle for total external reflection. As the ratio of the surface-bound species to the total number of species in the solution volume adjacent to the surface decreases, the FY distribution broadens at the low angles. A similar effect is noted when a diffuse layer accumulation arises due to an interfacial electrostatic potential. 

Besides the compartment analysis, non-compartment models can be used. One frequently used procedure is the regression method. This method performs a linear regression fit on a voxel basis. The slope image provides information about the trapping of the tracer, while the intercept image reflects the distribution volume of the radiopharmaceutical. Another non-compartment model is based on the calculation of the fractal dimension (FD) (17). FD is a parameter for the heterogeneity and is calculated for the time-activity data of each individual VOI. The values of FD vary from 0 to 2 showing the deterministic or chaotic distribution of the tracer activity. We use a subdivision of 7 x 7 and a maximal SUV of 20 for the calculation of FD. 

The next section is a summary of the bioavailability/pharmacokinetic data and the overall conclusions. The summary should include a table with the following pharmacokinetic parameters peak concentration (Cmax), AUC, time to reach peak concentration (Tmax), elimination constant (kel), distribution volume (Vd), plasma and renal clearance, and urinary excretion. Overall conclusions as well as any unresolved problems should be discussed. 

In this section we summarize the classical theory which assumes that, for sufficiently concentrated solutions, the distribution of segments throughout the solution is homogeneous, as if the coils could interpenetrate without any hindrcuice. This type of theory, which is known as a mean-Jield theory because all the segments experience, on average, the same force field, is expected to hold when the excluded volume parameter i is small. More recent theories for better solvents (higher u) will be treated in 5.2d. 

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). 

In contrast to elimination clearance, elimination half-life (b 72) is not a primary pharmacokinetic parameter because it is determined by distribution volume as well as by elimination clearance. 

Equation 2.4 was derived by substituting CLR/Vi for k in Equation 2.13. Although Ud and CLr are the two primary parameters of the single-compartment model/ confusion arises because k is initially calculated from experimental data. However/ k is influenced by changes in distribution volume as well as clearance and does not reflect just changes in drug elimination. 

Eactors to be considered in deciding whether or not inter species scaling would be predictive of human PK parameter estimates include (1) binding characteristics/ (2) receptor density/ (3) size and charge of molecule/ (4) end-terminal carbohydrate characteristics/ (5) degree of sialylatioii/ and (6) saturation of elimination pathways. These factors are known to influence clearance and distribution volumes/ as will be discussed in subsequent sections. Por example/ clearance may involve several mechanisms/ including immune-mediated clearance that results in nonconstant clearance rates. The interspecies predictability of clearance in this situation would be questionable. 

In the literature, one finds a bimodal distribution of parameter quality. On the one hand is the force field developer who makes monumental efforts to minimize the error between computed and experimental molecular properties. Parametarizations often involve fits to physical data such as molecular structure (bond lengths and bond angles), vibrational data, and heats of formation. Sometimes fittings also include molecular dipole moments, heats of sublimation, or rotational barriers from nuclear magnetic resonance or other spectroscopic measurements. Well-tested, high quality parameters are the result. Some of the better force fields were compared by Pettersson and Liljefors in Volume 9 of this series. ... 

Test Items. As a rule, the pharmacokinetic parameters of test substances such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax), area under curve (AUC), elimination half-life, clearance, distribution volume, bioavailability, etc., and pharmacokinetic nonlinearity are studied. The pharmacokinetics of metabolites of the test substance should be examined if necessary. 

In this model, the clearance of nellinavir is partitioned between the formation route of M8 via CYP 2C19 and all other routes of elimination of nellinavir via CYP 2D6, 2C9, and 3A4. The metabolic clearance of nellinavir to M8 and the distribution volume of M8 are not identifiable separately. The actual parameter estimated is the microrate constant K23, equal to the ratio of metabolic clearance of nellinavir to M8 to the distribution volume of M8. 

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

The URR is an easy calculation and thus is frequently used to measure the delivered dialysis dose. However, the URR does not account for the contribution of convective removal of urea. The Kt/V is the dialyzer clearance of urea K) in L/h multiplied by the duration of dialysis (/) in hours, divided by the urea distribution volume of the patient (V) in liters. Kt/Vi a unitless parameter that quantitates the fraction of the patient s total body water that is cleared of urea during a dialysis session. Urea kinetic modeling, using special computer software, is the optimal means to determine the Kt/V. Kt/V can also be calculated by using the following equation. ... 

Stem (1997) identified data on the distribution of parameters in the one-compartment model from the published literature. Blood volume and body weight were assumed to be correlated. A similar approach was used by Swartout and Rice (2000). In that analysis, however, some of the parameters are described by different distributional shapes or by distributions from different data sources than those used by Stem (1997). Swartout and Rice (2000) assumed correlations between several pairs of parameters the hair-to-blood ratio and the elimination-rate constant body weight and blood volume and the fraction of the absorbed dose in the blood and body weight. 

The effects of different model parameters on the plasma concentration versus time relationship can be demonstrated by mathematical analysis of the previous equations, or by graphical representation of a change in one or more of the variables. The model equations indicate the plasma concentration (C ) is proportional to the intravenous dosing rate ( o.iv) and inversely proportional to the compartment 1 distribution volume (Vi). Thus an increase in or a decrease in Vi both yield an equivalent increase in Cp, as illustrated in... 

The remaining model parameters still to be determined include the overall clearance (CL) and the two-compartment distribution volumes (Fi, V s, Vauc)-As in the one-compartment first-order absorption model, these remaining model parameters cannot be calculated until the bioavailability (F) has been evaluated. This will require AUC calculations and a comparison to IV drug delivery results, as described in the next two sections. 

---