Volumes of Distribution

Review of Elementary Concepts

Volume of distribution is a theoretical concept that may or may not correspond to the anatomical compartment(s) which drugs or metabolites may access after dosing. When size of the dose (D) is known, and when drug concentration (C) may be found by sampling biological fluids, then, in the simplest case, the volume of distribution (VD) is:

Clinical protocols can usually only prescribe the sampling of a subset of compartments when a drug is known to distribute widely in the body. For example, a lipophilic drug may penetrate lipo-philic organs such as brain, and, obviously, brain sampling simply for pharmacokinetic purposes is usually possible only in animals. In such cases, blood concentrations fall far lower than if the dose had distributed solely into the circulating compartment; C becomes very small, and VD becomes correspondingly very large. The opposite effect would require the drug to be restricted to a fraction of the compartment that is sampled, essentially suggesting that too few compartments have been postulated, and is almost never encountered. Again, see Curry (1980) or Benet et al (1996) for expansion of these elementary aspects of volume of distribution.

Prediction of Human Volumes of Distribution

The free (not plasma protein-bound) volume of distribution of experimental drugs is generally considered to be constant for all species. Thus, the volume of distribution in man can easily be predicted through a simple proportionality between in vitro plasma protein binding data in man and in a preclinical species, and in vivo volume of distribution in that same preclinical species:

KDhu

^preclinical species x fuh u /^preclinical species

Table 10.3 shows the predicted volume of distribution of a single intravenous bolus dose of Compound X in man; this is found by using the above equation, an in vitro estimate of protein binding data for rat and dog plasma, and the observed volumes of distribution for these two species in vivo. For man, VDhuman was predicted to be 3.48— 4.591 kg—1 using the rat data and 3.01 — 5.061 kg—1 using the dog data.

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