Tissue pharmacokinetics of clonidine in rats

The antihypertensive drug clonidine exhibits nonlinear pharmacokinetics in man and rats after intravenous injection. In order to define the basis of this nonlinearity, tissue kinetics of clonidine in rats were determined at three dose levels. It was found that tissue concentrations of clonidine were linearly related to dose increases in most organs with the exception of the heart, suggesting that there was a limited binding capacity in this organ. The rate of disappearance of clonidine from most tissues was best described by a monoexponential curve with half-lives of 30 to 120 min. An exception was the stomach, and clonidine accumulated in this organ, probably due to a pH partitioning effect of this weak base. Renal clearance of clonidine in rats was also examined and found to decrease by approximately 40% when the dose was increased from 50 microgram/kg to 250 microgram/kg. It was concluded that renal clearance and and possibly fecal clearance could explain the nonlinear pharmacokinetics of clonidine.