| Abstract: | The pharmacokinetics of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new antihypertensive agent, was studied in rats and dogs. The 14C-labelled compound was synthesized by a microscale procedure with 45% chemical yield and 98% radiochemical purity. In both animal species, MDL-899 was rapidly absorbed from the gastro-intestinal tract, achieving peak plasma levels in 0.5-2 h. The ratio between the plasma concentrations of 14C and of unchanged MDL-899 indicates rapid metabolic transformation and, especially in the rat, a marked first-pass effect. MDL-899 binds to serum proteins with a very low affinity and rapidly enters the tissue compartment, with large distribution volumes (1.6 l/kg rat, 2.0 l/kg dog). Target tissues in the rat were the liver, kidneys, adrenals, lungs, ovaries, uterus and the arterial walls, which constitute a deep-compartment. The plasma half-life of unchanged MDL-899 was 0.5 h in the rat and 1.4 h in the dog, while the terminal half-lives for total radioactivity were much longer (two elimination phases). Within the range of doses tested (1 and 40 mg/kg) there is evidence of non-linear kinetics (dog). The plasma kinetics profiles of both MDL-899 and 14C were the same in both males and females (rat). In both rats and dogs, elimination of the test dose was preferentially via the kidneys, as metabolites. The time course of the pharmacological response seems to be correlated to the kinetics of the active species in deep-compartment(s) rather than to the plasma concentration. |
