Volume of distribution at steady state

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]. 

V is the volume of distribution at steady state (in L kg-1) k is the elimination constant (this is given by clearance divided by volume) ... 

Distribution - The plasma protein binding of epierenone is about 50%. The apparent volume of distribution at steady state ranged from 43 to 90 L. Epierenone does not preferentially bind to red blood cells. 

Distribution - Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdgs) is approximately... 

The apparent volume of distribution at steady state of ertapenem is approximately 8.2 L. 

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. 

Distribution - The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses. Varying degrees of hepatic and renal insufficiency do not affect the protein... 

Pharmacology Trimetrexate, a 2.4-diaminoquinazoline, nonclassical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Pharmacokinetics Clearance was 38 15 ml /min/m and volume of distribution at steady state (Vdgs) was 20 8 L/m. The plasma concentration time profile declined... 

Pharmacokinetics A study of single IV infusions of 3 to 20 mg/kg in Crohn disease or RA patients showed a linear relationship between the dose and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. The median terminal half-life of infliximab ranged between 8 to 9.5 days. 

Zanamivir (2) is a potent competitive inhibitor of viral neuraminidase glycoprotein, which is essential in the infective cycle of both influenza A and B viruses. It inhibits a wide range of influenza A and B types in vitro as well as in vivo. The concentrations of inhibiting in vitro plaque formation of influenza A and B virus by 50% in Madin-Darby canine kidney (MDCK) cells were 0.004-0.014 p.mol/L in laboratory-passaged strains, and 0.002-16 p.mol/L in assays of clinical isolates. Due to its low bioavailability, it is delivered by inhalation via the Diskhaler , 10 mg twice daily, or intranasally 2-4 times daily for 5 days. After an intravenous dose of 1 -16 mg, the median elimination half-life was ti/2 = 7 h, the volume of distribution at steady state was Vdss = 16 L, and 90% of the dose was excreted unchanged in the urine. After intranasal and inhaled (dry powder) administration, maximum serum concentrations occurred within 2h and the terminal phase half-lives were 3.4 and 2.9 h, respectively. The bioavailabilities were 10 and 25%, respectively, and 20% after inhalation of zanamivir (2) by nebulizer. 

S Apparent Volume of Distribution at Steady State The volume of distribution that is determined when plasma concentrations are measured at steady state and in equilibrium with the drug concentration in the tissue compartment, VdtSS, is determined as... 

It is possible to predict what happens to Vd when fu or fur changes as a result of physiological or disease processes in the body that change plasma and/or tissue protein concentrations. For example, Vd can increase with increased unbound toxicant in plasma or with a decrease in unbound toxicant tissue concentrations. The preceding equation explains why because of both plasma and tissue binding, some Vd values rarely correspond to a real volume such as plasma volume, extracellular space, or total body water. Finally interspecies differences in Vd values can be due to differences in body composition of body fat and protein, organ size, and blood flow as alluded to earlier in this section. The reader should also be aware that in addition to Vd, there are volumes of distribution that can be obtained from pharmacokinetic analysis of a given data set. These include the volume of distribution at steady state (Vd]SS), volume of the central compartment (Vc), and the volume of distribution that is operative over the elimination phase (Vd ea). The reader is advised to consult other relevant texts for a more detailed description of these parameters and when it is appropriate to use these parameters. 

Traditionally, linear pharmacokinetic analysis has used the n-compartment mammillary model to define drug disposition as a sum of exponentials, with the number of compartments being elucidated by the number of exponential terms. More recently, noncompartmental analysis has eliminated the need for defining the rate constants for these exponential terms (except for the terminal rate constant, Xz, in instances when extrapolation is necessary), allowing the determination of clearance (CL) and volume of distribution at steady-state (Vss) based on geometrically estimated Area Under the Curves (AUCs) and Area Under the Moment Curves (AUMCs). Numerous papers and texts have discussed the values and limitations of each method of analysis, with most concluding the choice of method resides in the richness of the data set. 

The least-squares mean tasidotin total volume of distribution at steady state was 10 L, and was not affected by dose or day of administration. Between-subject variability was estimated at 39%. The tasidotin half-life did not change over day of administration, but increased with increasing dose (p < 0.0001) and decreased with increasing BSA (p = 0.0144). The least squares mean half-life was 26 min at 2.3 mg/m2, but was 46 min at 62.2 mg/m2. Between-subject variability was estimated at approximately 20%. The finding that the half-life was dose-dependent was not surprising, as total systemic clearance was affected by both dose and BSA, whereas volume of distribution at steady state was unaffected by dose or BSA. Under these conditions, the half-life would be expected to change inversely proportional to clearance. 

Abbreviations Crmx maximum cetuximab serum concentration AUCo-ob area under the concentration-time curve extrapolated to infinity CL total body clearance Vss volume of distribution at steady state terminal elimination half-life SD standard deviation. 

Values for mean volume of distribution at steady state (Vss) appeared to be independent of dose, and ranged from 1.99 to 2.88 L/m2 after the first dose of 20 to 500 mg/m2 of cetuximab (Fig. 14.5). These volumes are consistent with that of the vascular space, and in agreement with values of other IgGl-derived monoclonal antibodies. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

Decitabine (1) exhibits poor oral bioavailability and is consequently administered intravenously. It is rapidly eliminated in animals, with a half-life of 30 minutes in mice, 42 min in rabbits, and 75 min in dogs. For both rabbits and dogs, the apparent volume of distribution at steady state is 800 mL/kg. This is within the range of total body water and consistent with a weak protein-binding drug.12... 

In humans, the mean maximum plasma concentration (Cmax) is 79 ng/mL and the time to achieve Cmax was 2.67 h after a single 3-h infusion of decitabine (1) at 15 mg/m2. At this dose, the volume of distribution at steady state is 148 mL/kg, and the total plasma clearance is 122 L/kg/m2. The terminal half-life is approximately 35 min as decitabine (1) is primarily metabolized in the liver by cytidine deaminase to yield noncytotoxic 5-aza-2 -deoxyuridine. Urinary excretion of unchanged decitabine (1) is low (0.01-0.9% of total dose).13... 

The apparent volume of distribution of ciprofloxacin is 2-3.5 L/kg, and the apparent volume of distribution at steady state is 1.7-2.7 L/kg. Only low concentrations of ciprofloxacin are distributed into cerebrospinal fluid (CSF). Peak CSF concentrations may be 6-10% of peak serum concentrations. The drug is moderately bound to serum protein (16-43%), and crosses the placenta and is produced with the mammary milk [6, 10],... 

In this section, we describe a quantitative VD model on 118 chemically diverse drugs comprising neutral and basic compounds. VD data were collected from literature by Lombardo et al. [19]. In the vast majority of cases, these data represent VDss values, i.e. volume of distribution at steady state. 

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-... 

As discussed in Chapter 3, proteins and mABs distribute initially into the plasma volume and then more slowly into the interstitial fluid space. It can be seen from Table 32.11 that the initial distribution volume of interleukin-2 (IL-2) IL-12/ granulocyte colony-stimulating factor (G-CSF)/ and recombinant tissue plasminogen activator (rt-PA) approximates that of plasma volume. In contrast/ the initial distribution volume of FIX is approximately twice that of plasma volume. On the other hand/ the volumes of distribution at steady state (Vd(ss)) for IL-12/ G-CSF/ and rt-PA are considerably smaller than is the Vd(ss) of inuliii/ a marker for extracellular fluid space (ECF). When distribution volume estimates are much less than expected values for ECF/ they could reflect the slow transport of large molecules across membranes and the fact that either assay sensitivity or sampling time has been inadequate to characterize the true elimination phase of the compound. 

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