Complement inhibition by amidines and guanidines— in vivo and in vitro results

Amidines and guanidines have been reported to be effective inhibitors in vitro of complement. This study reports the in vivo activity of four such compounds, 4-aminobenzamidine, 3,4-dimethoxybenzamidine, 4-methyl-2-guanidinoquinazoline and pentamidine, as reflected in their ability to inhibit the Forssman reaction, a model of complement-mediated tissue damage. Inhibitory concentrations of each compound were first determined using whole guinea pig serum. In contrast to two other, known complement inhibitors, cobra venom factor and fumaropimaric acid, these compounds failed to block the Forssman reaction after intravenous administration at greater than their computed inhibitory concentrations. In addition, the serum from amidine-dosed guinea pigs failed to show complement inhibition, indicating that inhibitory concentrations had not been achieved in vivo. Confirming this, 4-aminobenzamidine was shown to partition out of blood into an apparent volume of distribution of ca. 2.7 liters/kg less than 2 min after an intravenous dose. Other amidines and guanidines, including pentamidine, show a correspondingly large volume of distribution. We conclude that this class of inhibitors must undergo structural modifications designed to produce adequate and sustained plasma concentrations before in vivo anticomplementary activity can be expected.