Kinetic studies of the tissue binding tendency of the new vasodilator pildralazine

Studies of the binding and release of the new antihypertensive drug (+/-)-1-[(6-hydrazinopyridazin-3-yl)methylamino]-2-propanol (pildralazine, PD) were performed on isolated perfused guinea pig hearts according to the Langendorff technique. Extensive binding to and accumulation in the tissue were recorded. Even after 30 min of washout considerable PD concentrations were detected both in the myocardium (900 ng/g w.w.) and the effluent (17 ng/ml = 100 ng/min). The calculation of elimination half-life yielded a nearly identical value in the myocardial tissue and the effluent. Coronary vasodilation mediated by PD ran in close parallel to the drug concentrations. As the washout of [3H]-sucrose as an extracellular space marker was half-maximal already after 1.6 min rediffusion of PD originated from tissue sites and not only by dilution of the fluid in the extracellular space. In addition the results indicated that the observed binding of PD to cell structures prevented its normally rapid chemical destruction, already evident in aqueous solutions. The back diffusion of PD from the binding and storage sites into the coronary perfusate was very slow, explaining its long-lasting biological availability and action in vivo. The release kinetics may be described by an exponential function which obeys the criterions of a first order elimination process.