Low oral bioavailability of dihydroergotamine and first-pass extraction in patients with orthostatic hypotension.

The relative importance of the effect of absorption and first-pass extraction in bioavailability and clinical effectiveness of oraldihydroergotamine (DHE) was examined in six subjects with orthostatic hypotension. Maximum increases in systolic blood pressure of standing subjects occurred within 15 min of intravenous administration (10 micrograms/kg); after 30 min pressure declined linearly with respect to time over the ensuing 3 hr. Plasma DHE concentrations declined biexponentially with respect to time. Mean plasma half-life was 2.15 hr and plasma clearance averaged 862 ml/min. There was no rise in "standing" systolic blood pressure on oral administration (200 to 600 micrograms/kg). Peak plasma concentrations ranged from less than 0.1 to 2 ng/ml. Apparent oral absorption for DHE ranged from 19.5% to 53.3% while systemic bioavailability varied from less than 0.1% to 1.5%. when glyceryl trinitrate was taken orally with DHE, the bioavailability of the latter increased between 56% and 370% over the 0.1% to 1.5% without any apparent alteration in DHE absorption. Standing systolic blood pressure increased 27% (P less than 0.05) 2 hr after the same doses of DHE with glyceryl trinitrate. These findings suggest that the extent of first-pass extraction by the liver is the prime determinant of DHE bioavailability after oral administration and that factors that alter gastrointestinal and portal vein flow to the liver affect its bioavailability.