Volume of Distribution and Duration

The volume of distribution of a drug molecule is, as described previously, a theoretical number that assumes the drug is at equal concentration in the tissue and in the circulation and represents what volume (or mass) of tissue is required to give that concentration. Volume of distribution, therefore, provides a term that partially reflects tissue affinity. However, it is important to remember that affinity may vary between different tissues and a moderate volume of distribution may reflect moderate concentrations in many tissues or high concentrations in a few. For an illustration of

Fig. 4.6 Free (unbound) volumes of distribution of neutral (triangles) and basic (squares) drugs, also indicating amlodip-ine and nifedipine together with their free (unbound) clearance value (Clu).

how the manipulation of distribution affects systemic concentration the following examples will use free volume rather than total, although either could equally apply.

Taking the simplest case of neutral drugs, where increasing log D74 reflects increased binding to constituents of blood and cells and increased partitioning of drugs into membranes, there is a trend for increasing volume of distribution with increasing lipophilicity (Figure 4.6). In this case, for uncharged neutral molecules, there are no additional ionic interactions with tissue constituents. In most cases, the volume of distribution is highest for basic drugs ionized at physiological pH, due to ion-pair interactions between the basic centre and the charged acidic head groups of phospholipid membranes as described previously.

This ion pairing for basic drugs results in high affinity and also ensures that the ionized fraction of the drug is the predominant form within the membrane. This is particularly important, since most alkylamines have pKa values in the range 8-10 and are thus, predominantly in ionized form at physiological pH. The increase in volume for basic drugs is also illustrated in Figure 4.6.

The importance of volume of distribution is in influencing the duration of the drug effect. Since half-life (0.693/kel where kel is the elimination rate constant) is determined by the volume of distribution and the clearance (Clu = Vdf x kel), manipulation of volume is an important tool for changing duration of action. Here the small amount of drug in the circulation is important, since this is the compound actually passing through and hence available to the organs of clearance (liver and kidney). Incorporation of a basic centre into a neutral molecule is therefore a method of increasing the volume of distribution of a compound. An example of this is the discovery of the series of drugs based on rifamycin SV (Figure 4.7). This compound was one of the first drugs with high activity against Mycobacterium tuberculosis. Its clinical performance [11], however, was disappointing due to poor oral absorption (dissolution) and very short duration ascribed at the time to rapid biliary elimination (clearance).

Many different analogues were produced, including introduction of basic functions with a goal of increased potency, solubility, and reduction in clearance. Ri-fampicin is a methyl-piperazinyl amino methyl derivative [12] with much better duration and has become a successful drug. The basic functionality however does not alter clearance but increases volume substantially (Figure 4.7). Duration is enhanced further [12] by the more basic spiropiperidyl analogue, rifabutin (Figure 4.7). Again

■.3 Volume of Distribution and Duration 53

the desirable pharmacokinetic (and pharmacodynamic) properties are due to effects on volume of distribution rather than effects on clearance.

This strategy of modification of a neutral molecule by addition of basic functionality was employed in the discovery of the dihydropyridine calcium channel blocker, amlodipine. The long plasma elimination half-life (35 h) of amlodipine (Figure 4.8) is due, in large part, to its basicity and resultant high volume of distribution [13].

Fig. 4.8 Structures of the dihydropyridine calcium channel blockers, nifedipine (neutral) and amlodipine (basic).

These pharmacokinetic parameters are unique among dihydropyridine calcium channel blockers and allow once-a-day dosing of amlodipine, without the need for sustained release technology. The large volume of distribution is achieved despite the moderate lipophilicity of amlodipine and can be compared to the prototype dihydropyridine drug, nifedipine which is of similar lipophilicity but neutral (Figure 4.8). Notably, these changes in structure do not trigger a large change in clearance. The high tissue distribution of amlodipine is unique amongst dihydropyridine drugs, and has been ascribed to a specific ionic interaction between the protonated amino function and the charged anionic oxygen of the phosphate head groups present in the phospholipid membranes [14] and is as described previously in Chapter 1 (Physicochemistry).

Another basic drug where minor structural modification results in a dramatic increase in volume of distribution is the macrolide antibiotic, azithromycin. The traditional agent in this class is erythromycin, which contains one basic nitrogen, in the sugar side-chain.

Introduction of a second basic centre into the macrolide aglycone ring in azithromycin increases the free (unbound) volume of distribution from 4.8 to 62 L kg-1 (Figure 4.9). Free (unbound) clearance of the two compounds is also changed from 55 mL min-1 kg-1 for erythromycin to 18 mL min-1 kg-1 for azithromycin. The apparent plasma elimination half-life is, therefore, increased from 3 to 48 h. One consequence of the high tissue distribution of azithromycin is that the plasma or blood concentrations do not reflect tissue levels, which may be 10-to 100-fold higher, compared to only 0.5- to 5-fold higher for erythromycin. Azithromycin readily enters macrophages and leukocytes and is, therefore, particularly beneficial against intracellular pathogens. Elimination of azithromycin is also prolonged with reported tissue half-life values of up to 77 h [15]. Overall, the pharmacokinetic properties of azithromycin provide adequate tissue concentrations on a once-daily dosing regimen and provide wide therapeutic applications. The high and prolonged tissue concentrations of azithromycin achieved provide a long duration of


Fig. 4.9 Structures of the macrolide antibiotics, erythromycin (monobasic) and azithromycin (dibasic).

erythromycin azithromycin

Fig. 4.9 Structures of the macrolide antibiotics, erythromycin (monobasic) and azithromycin (dibasic).

4.3 Volume of Distribution and Duration 55

4.3 Volume of Distribution and Duration 55

Fig. 4.10 Structures of codeine (monobasic) and pholcodine (dibasic).

oh codeine pholcodine

Fig. 4.10 Structures of codeine (monobasic) and pholcodine (dibasic).

action. Only 3-5-day courses of treatment are therefore required, hence improving patient compliance to complete the course and reducing the development of resistance [15].

A similar example to azithromycin, but in a small molecule series is pholcodine (Figure 4.10), where a basic morpholino side chain replaces the methyl group of codeine. Unbound clearance is essentially similar (10 mL min-1 kg-1) but the free unbound volume is increased approximately 10-fold (4 to 40 L kg-1) with a corresponding increase in half-life (3 to 37 h) [16].

High accumulation of drug in tissues has also been implicated in the seven-fold longer elimination half-life of the dibasic antiarrhythmic, disobutamide (Figure 4.11) compared to the monobasic agent, disopyramide. The elimination half-life of disobutamide is 54 h compared to approximately 7 h for disopyramide.

Disobutamide has been shown to accumulate extensively in tissues in contrast to disopyramide [17].

It is important to note that in these latter two examples, the high tissue affinity of the well-tolerated, anti-infective, azithromycin, is viewed as a pharmacokinetic advantage, while similar high tissue affinity is viewed as disadvantageous for the an-tiarrhythmic, disobutamide, which has a low safety margin. Obviously, different therapeutic areas impose different restrictions on the ideal pharmacokinetic profile for management of each condition, hence careful consideration should be paid to this at an early stage in drug discovery programmes.

of the monobasic antiarrythmic, disopyramide and the dibasic analogue disobutamide.

Fig. 4.11 Structures

Fig. 4.11 Structures

disopyramide disobutamide

56 I 4 Distribution 4.4

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