DISTRIBUTION OF INHIBITORS IN ANIMALS 399 



duced into the circulation by intravenous injection, the initial distribution 

 will depend in part on the blood supply to the tissues; when slow absorption 

 occurs, there may be time for other factors to become important. This is 

 illustrated best by a drug, such as thiopental, which, when given intrave- 

 nously, is present in the brain in relatively high concentrations so that anes- 

 thesia is produced, but which is slowly redistributed in the body, as the 

 result of its high lipid solubility, the brain concentration decreasing with 

 time. A very slow intravenous administration would not produce the char- 

 acteristic initial distribution seen on more rapid injection and much more 

 would have to be present in the body to achieve a comparable central de- 

 pression. The variations in time of the tissue concentrations of isoniazid and 

 acetazolamide described above may be due to such redistribution factors. 



Finally, the distribution of an inhibitor may depend on the concentra- 

 tion present in the circulating blood, especially in situations in which the 

 inhibitor is producing differential effects in the tissues. This may be termed 

 the concentration factor. The plasma concentration of inhibitor will, of 

 course, vary with the route of administration. This factor is related to the 

 effect of dosage on the distribution. 



Dose of the Inhibitor 



If penetration of an inhibitor into tissues were a simple matter of dif- 

 fusion dependent on concentration gradients, one might expect that the 

 distribution pattern would not vary with the dosage within limits. Although 

 this may be true in some instances, there is much evidence that more com- 

 plex situations are common. There is little experimental evidence from 

 inhibitors, but several drug studies have shown that changing distribution 

 occurs with increasing dosage. Analysis of the data from studies of Paludrine 

 ( chlorguanide ) in rat tissues (Schmidt et al., 1947), although suffer- 

 ing from a limited number of animals, shows that the differences between 

 tissues became progressively greater as the dose was increased. The liver/ 

 brain ratio rose progressively from 1.4 to 30 as the dose was increased from 

 11 to 91 mg/kg. 



The fact that the concentration of drug or inhibitor in a tissue is not 

 linearly proportional to the dose also indicates complexities in the be- 

 havior of these substances in the body. When acetazolamide was given 

 orally to mice and the concentrations in brain determined (Millichap et al., 

 1955), as the dose was increased from 25 to 400 mg/kg, the concentration in 

 the brain rose more slowly, so that on the average for every doubling of 

 the dose, the brain concentration increased by a factor of 1.21. 



The reasons for these deviations are to be found in the saturation of 

 binding sites for inhibitors, the different rates of inactivation or chemi- 

 cal modification of the inhibitor at different dosage levels, active proc- 

 esses in inhibitor uptake, and the failure of the concentration of free drug 



