Central dopamine agonistic activity and microsomal biotransformation of lisuride, lergotrile and bromocriptine.

Lisuride (0.05 – 0.1 mg/kg), lergotrile (1 mg/kg) and bromocriptine (5 mg/kg) reduced the turnover of dopamine (DA) in rat brain, as indicated by a pronounced decrease of cerebral homovanillic acid (HVA) without appreciable changes in DA level. Time curves revealed that lisuride injected intracerebroventricularly or i.p. caused a rapid reduction of HVA lasting for a few hours, whereas after p.o. administration the decrease of HVA was delayed. Pretreatment of the rats with the microsomal enzyme inhibitor proadifen potentiated and prolonged, rather than prevented, the effect of i.p. injected lisuride on rat cerebral DA turnover. The HVA reduction obtained with lergotrile and bromocriptine was also somewhat retarded after p.o. administration; the HVA diminution seen after i.p. injection was again potentiated and prolonged by proadifen. In addition, this microsomal enzyme inhibitor prolonged and intensified, rather than prevented, the hypothermic effect of all of the 3 ergolines. It is concluded that, in the rat, the central DA agonistic activity of the ergolines studied is caused by the drugs themselves and does not require previous biotransformation into active metabolites. The retarded onset and the prolonged duration of action after oral administration is probably due to slow intestinal absorption and slow microsomal inactivation, respectively.