Distribution of drugs volume

Along with clearance, volume of distribution determines the pharmacokinetic behavior of a drug. Volume of distribution is an attempt to describe how a drug disperses throughout the various tissues of the body. 

Quite often, the half-life of a drug is used as an indicator of systemic exposure. It is determined by clearance and volume of distribution. While clearance describes the ability of the body to eliminate the drug, volume of distribution (Vd) is the pharmacokinetic parameter that provides an estimate of the extent of distribution of the drug into the tissue compartments. 

Neutral compounds interact with the lipid portion of membranes and albumin. Both relationships are related to the lipophilicity of the drug. Volumes of distribution will generally be of the order of 0.7 1/kg. 

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. 

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]. 

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... 

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. 

Clearance is a critical parameter because of its role in determining a drug s dose size and frequency. First-pass clearance in combination with absorption determines a compound s bioavailability. Clearance and absorption in combination with potency determine dose size. Clearance and volume of distribution determine half-life, and thus dosing frequency. 

Because disturbances in fluid balance are routinely encountered in clinical medicine, it is essential to have a thorough understanding of body fluid compartments and the therapeutic use of fluids. Similarly, disturbances in serum sodium, potassium, calcium, phosphorus, and magnesium are ubiquitous and must be mastered by all clinicians. Dysregulation of fluid and/or electrolyte status has serious implications regarding the concepts of drug absorption, volumes of distribution, and toxicity. Similarly, many medications can disrupt fluid and/or electrolyte balance as an unintended consequence. 

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... 

Certain patient populations require special considerations due to their altered metabolism, unique volume of distribution, or increased risk for side effects.43 Although many of these patients are excluded from clinical trials in SE, the standard algorithm for SE still applies for these patients in terms of immediate care, assessment, and drugs (see Table 28-2). 

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... 

Example. Sulfadiazine in a normal volunteer had a biological half-life of 16 hours and a volume of distribution of 20 L. Sixty percent of the dose was recovered as unchanged drug in urine. Calculate TCR, RCR, and MCR for sulfadiazine in this person. 

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. 

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