Prediction of the volume of distribution of a drug:: which tissue-plasma partition coefficients are needed?

The aim of this study was to identify the tissue-plasma partition coefficients (K-p) needed for an initial prediction of the volume of distribution at steady state (Vd(ss)) of a drug in humans. Values of K-p were collected from the literature. Only K-p values plausibly representing true steady state distribution were accepted, and data had to be available for muscle, fat, skin and at least five other organs. The apparent volume of distribution of a drug in an organ/tissue (V-app) was calculated as K-p multiplied by the volume of the organ/tissue, and the V-dss as the sum of all available V-app values. The percentage contribution of each V-app to the Vd(ss) was estimated. in addition, linear regressions were calculated values of all drugs in a specific organ/tissue and K-p in muscle or fat. Finally, the Vd(ss) was between K-p re-calculated using (for basic drugs) the K-p in fat to calculate V-app in fat and lungs and the K-p in muscle for the V-app of all other organs/tissues. The two sets of estimates of Vd(ss) were compared by linear regression. The same calculations were performed for acidic drugs, except that muscle K-p was used also for the lungs. Distribution to fat and muscle accounted for 84% (61-91%) (median and range) of the total estimated Vd(ss) of the basic drugs (n = 17). The regressions between K-p in organs/tissues and muscle K-p were statistically significant except in the case of liver. For acidic drugs (n = 18), distribution to fat and muscle accounted for 65% (42-92%) of Vdss, and the regressions of K-p were significant for all organs/tissues except kidney and bone. For both types of drugs, correlations between organ/tissue K-p values and K-p in fat were generally worse. There were excellent linear correlations between Vd(ss) calculated by means of only two K-p values and the originally calculated Vd(ss) (r(2) greater than or equal to 0.99 for both basic and acidic drugs; slopes were not significantly different from unity). Thus, initial estimation of the Vd(ss) of a new drug can normally be based on only two K-p values, those of muscle and fat. The muscle K-p can be used to represent all lean tissues, including the residual "carcass", with the exception that fat K-p can be used for distribution of basic drugs to lungs.