The distribution pattern of radioactivity across different tissues in quantitative whole-body autoradiography (QWBA) studies.
This study explored whether common rules exist for the distribution patterns across tissues in tissue distribution studies. To investigate this we tested whether tissue:plasma partition coefficients (PCs) of radioactivity are correlated with muscle:plasma PCs. The relationships between PCs of radioactivity in muscle and those in other tissues were investigated in 25 tissues for 20 structurally unrelated drug candidates. Tissue distribution data were obtained by quantitative whole-body autoradiography. Linear regression analysis was performed for each tissue. Radioactivity from basic and acidic/neutral compounds was analyzed separately. Results for acidic/neutral compounds: for the majority of the tissues investigated, the tissue:plasma PCs were well correlated with muscle:plasma PCs (R2 > 0.7). Correlations were worse (R2 < 0.7) in blood, white fat, excretory organs and tissues protected by a penetration barrier (e.g. brain). Slope factors for the regression ranged from 0.2 (blood) to 3.8 (Harderian gland) and were correlated with neutral lipid contents in tissues. Results for basic compounds: in most tissues, slope factors appeared to be higher than for acidic/neutral compounds. Correlations, however, were poorer than for acidic/neutral compounds. Overall, the present study demonstrates that muscle:plasma PCs are indicative of the overall tissue distribution of drug-related material, as they are well correlated with tissue:plasma PCs in most other tissues. Correlations for acidic/neutral compounds differ from those for basic compounds. The found PC relationships provide an explanation for the distribution pattern across tissues usually seen in tissue distribution studies.
Richter
Wolfgang F
WF
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Drug Metabolism and Pharmacokinetics, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. wolfgang.richter@roche.com
Starke
Volkmar
V
Whitby
Brian
B
D000818:Animals; D001345:Autoradiography / Q000706:statistics & numerical data*; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D006863:Hydrogen-Ion Concentration; D008297:Male; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D014018:Tissue Distribution
D019275:Radiopharmaceuticals