PLASMA-PROTEIN BINDING OF THE EXPERIMENTAL ANTITUMOR AGENT ACRIDINE-4-CARBOXAMIDE IN MAN, DOG, RAT AND RABBIT

The plasma binding of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) was investigated in-vitro by equilibrium dialysis for 3 h at 37 degrees C against isotonic phosphate buffer (pH 7.35) using [H-3]AC. T here were significant species differences with the smallest % free fra ction (mean +/- s.d.) occurring in human plasma (3.4 +/- 0.2), followe d by dog (8.1 +/- 0.4), mouse (14.8 +/- 0.8), rat (16.3 +/- 0.9) and r abbit (20.2 +/- 0.7). In plasma from healthy individuals (n=5), the % free fraction ranged from 2.7 to 3.8. In physiological solutions of hu man proteins, the greatest binding was observed for eel-acid glycoprot ein (AAG) (0.75 g L(-1)) with a mean free fraction of 24.1 +/- 2.2%, f ollowed by albumin (40 g L(-1)) with 31.6 +/- 0.7 and 39.8 +/- 2.5% fo r fatty-acid-free and globulin-free, respectively. There was also some binding to globulins (5 g L(-1)) with a mean % free fraction of 70.3 +/- 1.6 and 84.8 +/- 2.2 for Cohn's fraction I and IV, respectively. B inding data from the displacement of [H-3]AC by increasing concentrati ons of AC in human AAG (0.75 g L(-1)) or albumin solution (40 g L(-1)) indicated that AAG had 10-fold greater binding affinity for AC (K-a, 7.8 x 10(4) M(-1)) compared with albumin (K-a, 6.8 x 10(3) M(-1)). In human plasma enriched with AAG there was a signifiant negative linear correlation (r=0.92; P<0.001) between % AC free fraction and increasin g AAG concentration over the range 0.6-4.5 g L(-1). Small but signific ant (P<0.05) increases in AC free fraction occurred in the presence of various metabolites (50 and 100 mu M) but, of those tested, only N-mo nomethyl-acridine carboxamide increased the free fraction to the same extent as parent AC.