In rabbits, clonidine (200 micrograms/kg) exerted no blood pressure lowering effect after oral administration contrary to the strong decrease in blood pressure after i.v. injection. This surprising effect induced experiments on metabolic degradation of clonidine in the rabbit. After oral administration 14C-clonidine was rapidly almost totally metabolised and only minimal concentrations could be detected in the brain. In the urine (24-h collection) no clonidine was detected after oral dosing. In contrast, 15 min after i.v. injection 30% of radioactivity was unchanged clonidine in the plasma. In the brain 70% of the radioactivity during the first 2 h was clonidine. In accord with this, in the urine 22% of the dose administered was excreted as clonidine. From these experiments it is concluded that predominantly unchanged clonidine penetrates the blood-brain barrier. So the lack of effect after oral clonidine depends on the too low concentration of clonidine in the brain. To assess the pharmacological activity of clonidine metabolites identified in rabbit and other species including man, seven different compounds were injected to rabbits either systemically (i.v.) or intracisternally (i.c.i). Only p-hydroxy-clonidine-hydrobromide (St 666) induced weak blood pressure decreases after i.v. and strong ones after i.ci. injection, but to a lesser extent than clonidine itself.