PHARMACOKINETICS OF ACRIDINE-4-CARBOXAMIDE IN THE RAT, WITH EXTRAPOLATION TO HUMANS

The pharmacokinetics of N-[2-(dimethyl-amino)ethyl]acridine-4-carboxam ide (AC) were investigated in rats after i.v. administration of 18, 55 and 81 mumol/kg [H-3]-AC. The plasma concentration-time profiles of A C (as measured by high-performance liquid chromatography) typically ex hibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mea n (+/- SD) model-independent pharmacokinetic parameters were: clearanc e (Cl), 5.3 +/- 1.11 h-1 kg-1; steady-state volume of distribution (V( ss)), 7.8 +/- 3.0 1/kg; mean residence time (MRT), 1. 5 +/- 0.4 h; and terminal elimination . half-life (t1/2Z), 2.1 +/- 0.7 h (n = 10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1-8 h after AC administration. By 6 h, plasma radioactivity concentration were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometri c equations were developed from rat and mouse pharmacokinetic data tha t predicted a Cl value of 0.075 (range, 0.05 -0. 10; 95% confidence li mits) 1 h-1 kg-1 and a V(ss) value of 0.63 (range, 0.2 - 1. 1) 1/kg fo r total drug concentrations in humans.