Plasma protein binding of the experimental antitumour agent acridine-4-carboxamide in man, dog, rat and rabbit.

Abstract

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 [3H]AC. There were significant species differences with the smallest % free fraction (mean +/- s.d.) occurring in human plasma (3.4 +/- 0.2), followed by dog (8.1 +/- 0.4), mouse (14.8 +/- 0.8), rat (16.3 +/- 0.9) and rabbit (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 human proteins, the greatest binding was observed for alpha 1-acid glycoprotein (AAG) (0.75 g L-1) with a mean free fraction of 24.1 +/- 2.2%, followed by albumin (40 g L-1) with 31.6 +/- 0.7 and 39.8 +/- 2.5% for 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. Binding data from the displacement of [3H]AC by increasing concentrations 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 (Ka, 7.8 x 10(4) M-1) compared with albumin (Ka, 6.8 x 10(3) M-1). In human plasma enriched with AAG there was a significant negative linear correlation (r = 0.932; P < 0.001) between % AC free fraction and increasing AAG concentration over the range 0.6-4.5 g L-1.(ABSTRACT TRUNCATED AT 250 WORDS)