Drug distribution apparent volume

Some relevant volumes of body compartments are (in liters) plasma water (3), erythrocyte water (3), extracellular water excluding blood (11), and intracellular water (24). The total body water is approximately 41 L. A comparison of selected drugs with apparent volumes of distribution (in liters) approximating various body compartments is shown in Table 2.6. 

Gibaldi M, Koup JR. Pharmacokinetic concepts Drug binding, apparent volume of distribution and clearance. Eur J Clin Pharmacol 1981 20 299-305. 

The 50 mg aminophylline (salt value, 0.85) represents 42.50 mg theophylline. Therefore, dose of theophylline is 42.5 mg and initial theophylline plasma concentration (from the intercept on the y-axis of the concentrationtime plot) is 4.8 igmL . Like other fundamental pharmacokinetics parameters of a drug, the apparent volume of distribution is also independent of the dose administered, route of administration and the chosen dosage form of a drug. 

Equations 10.14, 10.15 and 10.17 clearly suggest that the computation of the loading dose necessary to attain the desired plasma concentration of a drug instantaneously requires the knowledge of two fundamental pharmacokinetic parameters of a drug the apparent volume of distribution and/or the elimination half life. 

From this equation, we can see that the degree to which an increase in the fraction of drug unbound in the plasma will tend to increase a drug s apparent volume of distribution is dependent on the size of the ratio of the fraction of drug unbound in the plasma to the fraction unbound in the tissues ifupifut)- For the case of a drug with a small volume of distribution, this ratio is small. 

Volume of distribution Apparent volume to which a dose of drug distributes at the time of injection or administration. 

Oxcarbazepine Modulate sodium channels Loading dose Not recommended due to excessive adverse effects Maintenance dose 600-1200 mg/day. Start at 300 mg twice daily and titrate upward as indicated by response Half-life Not established Parent drug 2 hours 1 0-monohydroxy metabolite 9 hours Apparent volume of distribution 0.5-0.7 L/kg Protein binding 40% Primary elimination route Hepatic Diplopia, dizziness, somnolence Hyponatremia, 25-30% cross sensitivity in patients with hypersensitivity to carbamazepine... 

A discussion of all the reasons for this phenomenon is beyond the scope of this chapter, but a simple example will illustrate the concept. Highly lipid-soluble drugs, such as pentobarbital, are preferentially distributed into adipose tissue. The result is that plasma concentrations are extremely low after distribution is complete. When the apparent volumes of distribution are calculated, they are frequently found to exceed total body volume, occasionally by a factor of 2 or more. This would be impossible if the concentration in the entire body compartment were equal to the plasma concentration. Thus, Vd is an empirically fabricated number relating the... 

A is a function of the two rate constants (ka and kei), the apparent volume of distribution (Vd), and the amount of drug absorbed (Dg). After ka and kei have been evaluated and A has been determined by extrapolation, a value for Vd can be calculated if it is assumed that Dg is equal to the dose administered, i.e., absorption is 100% complete. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

The apparent volume of distribution (Vj) of the drug in this patient was approximately... 

The plasma concentration of a drug immediately following a 50-mg intravenous bolus dose of the drug was found to be 0.84 mcg/mL. What is the apparent volume of distribution of the drug ... 

Apparent volume of distribution of free (unbound) drug Maximum rate of reaction (Michaebs-Menten enzyme kinetics) Dosing interval in terms of half-life (= Tjtip)... 

The concentration (c) of a solution corresponds to the amount (D) of substance dissolved in a volume (V) thus, c = D/V. If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calculated from V = D/c. However, this represents an apparent volume of distribution (Vapp), because an even distribution in the body is assumed in its calculation. Homogeneous distribution will not occur if drugs are bound to cell membranes (5) or to membranes of intracellular organelles (6) or are stored within the latter (7). In these cases, Vapp can exceed the actual size of the available fluid volume. The significance of Vapp as a pharmacokinetic parameter is discussed on p. 44. 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Absorption/Distribution - Oral procainamide is resistant to digestive hydrolysis, and the drug is well absorbed from the entire small intestinal surface, but individual patients vary in their completeness of absorption. Following oral use, plasma levels peak at approximately 45 to 120 minutes. Following IM injection, plasma levels peak in 15 to 60 minutes. IV use can produce therapeutic plasma levels within minutes. About 15% to 20% is reversibly bound to plasma proteins. The apparent volume of distribution eventually reaches approximately 2 L/kg with a half-life of approximately 5 minutes. 

So, very simply, we have already calculated an apparent volume of distribution for our drug - one of the three variables (input, loss, volume) that determines the plasma concentration of the drug. 

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