398 8. INHIBITOR DISTRIBUTION IN LIVING ORGANISMS 



greater selectivity could be demonstrated. An analysis of the total brain, 

 as is often made, is then only a weighted average of the component regions. 

 The distribution of acetazolamide in the ocular tissues of the rabbit may 

 also be mentioned (Ballintine and Maren, 1955). After 10-20 mg/kg of 

 acetazolamide were given intravenously, the concentrations in micrograms 

 per gram of tissue or fluid from 20-120 min were roughly: aqueous humor, 

 0.64; lens, 0.73; iris, 1.4; ciliary process, 4.1; and plasma, 13.4. This distribu- 

 tion is of interest in understanding the mechanism by which acetazolamide 

 alters the formation of aqueous humor and the intraocular pressure. It is 

 now necessary to discuss some of the factors that are involved in producing 

 the inhomogeneous patterns of distribution described. 



Route of Administration of the Inhibitor 



The manner in which the inhibitor is introduced into the animal can in- 

 fluence the distribution in three ways. An inhibitor cannot be simultane- 

 ously presented in equal concentration to all the cells of a complex animal 

 but enters into the body through specific channels. This may simply be 

 called the spatial factor. When an inhibitor is given intravenously, it 

 will be picked up by the cells in those tissues through which the blood flows 

 and thus there will be usually a progressive decline in blood concentration 

 of inhibitor within the circulation. In some cases, the inhibitor may be 

 almost completely extracted from the blood stream before it reaches certain 

 tissues. Thus the initial distribution will depend on the site of injection 

 and the rate of the injection. This factor has been taken advantage of in 

 the use of certain drugs, where an action limited to a particular tissue is 

 desired (the slow injection of a nitrogen mustard into an artery supplying 

 the organ containing a tumor or the injection of vasodilators into the limb 

 arteries in peripheral vascular disease). It is possible that such a technique 

 might often be useful in inhibitor studies, especially combined with tempo- 

 rary occlusion of the vessels through which the blood leaves the tissue. 

 The slow injection of a mercurial into one renal artery, producing diuresis 

 only in that kidney, would be an example of the successful use of this tech- 

 nique. Similar concepts apply to all other routes of administration, with 

 the additional factor that some inhibitor may be taken up before it enters 

 into the circulation. Intramuscular or subcutaneous injection often leads 

 to marked uptake and effects locally, while oral administration can lead to 

 high concentrations of the inhibitor in the intestinal wall. An inhibitor 

 that is absorbed from the intestine passes through the liver immediately 

 and may be accumulated there initially, either to affect the liver or to be 

 metabolized by the multitudinous hepatic enzyme systems. 



The rates at which inhibitors enter the systemic circulation vary with 

 the route of administration and the distribution may depend on such rates. 

 This may be called the temporal factor. If an inhibitor is suddenly intro- 



