Investigation of the venoconstrictor effect of 8? hydroxydihydroergotamine, the main metabolite of dihydroergotamine, in man

Abstract

Summary The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8′ hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 µg into superficial hand veins. Both dihydroergotamine and 8′ hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8′ hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5–7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.