Biotransformation of urapidil: metabolites in serum and urine and their biological activity in vitro and in vivo.

: The biotransformation products of the antihypertensive drug urapidil were determined in the serum and urine of rat, dog and man. Comparison of the pattern of urapidil metabolism revealed that all species examined formed the same metabolites. However, quantitative differences were noted. The pattern of metabolites in serum was seen to parallel the excretion of urapidil and its metabolites in urine. The p-hydroxylated urapidil (M1) was found to be the predominant metabolite in man, the uracil-N-demethylated metabolite (M3) in dog, and M1 as well as the O-demethylated urapidil (M2) were found to be important in the rat. Furthermore, trace amounts of the urapidil-N-oxide (M5) are found in dog urine. As determined in the isolated rat vas deferens preparation, urapidil and the synthetized metabolites M1, M2, M3 and M5 are competitive antagonists of the effects of noradrenaline at postsynaptic alpha 1-adrenoceptors. Metabolites M2 and M3 exhibit alpha 1-adrenoceptor antagonism (pA2 values of 6.79 and 6.93 respectively) which are comparable to urapidil (pA2 = 7.02), whilst M1 and M5 are less potent antagonists giving pA2 values of 5.69 and 5.55 respectively. On i.v. or i.j. administration of urapidil, M1, M2, M3 or M5 to anaesthetized, normotensive rats, or orally to conscious spontaneously hypertensive rats, differences in cardiovascular responses were seen. Whilst M1 had little antihypertensive activity, M2 and M3 lowered blood pressure to a similar extent to that seen with urapidil. However, the duration of activity observed was shorter. Urapidil-N-oxide (M5) appeared to possess hypotensive activity comparable to urapidil, but examination of serum samples following the administration of M5 yielded mainly urapidil, suggesting that M5 exhibits its activity following reduction back to urapidil. In view of the serum levels attained and of the biological activity, the metabolites of urapidil do not appear to contribute significantly to the cardiovascular effects of urapidil in man or rat. However, in view of the serum levels and duration of M3 observed in dogs, this metabolite may make a significant contribution to the hypotensive activity of urapidil in this species.