Dihydroergotamine: discrepancy between arterial, arteriolar and pharmacokinetic data.
OBJECTIVE
To investigate the peripheral vascular effects and pharmacokinetics of dihydroergotamine (DHE) 0.5 mg after a single subcutaneous administration in humans.


METHODS
A double-blind, placebo-controlled cross-over study was performed in 10 healthy male subjects. A wash-out period of 2 weeks separated the two study periods. During each period, just before and at regular intervals after drug administration, vascular measurements were performed and venous blood samples were drawn. Vessel wall properties were assessed at the brachial artery, by ultrasound and applanation tonometry. Blood pressure and heart rate were recorded with an oscillometric device. Forearm blood flow was measured with venous occlusion plethysmography. For all parameter-time curves the area under the curve (AUC) was calculated. Differences in AUC after placebo and DHE (DeltaAUC) were analysed and the time-course of the difference assessed. DHE pharmacokinetics were analysed according to a two-compartment open model with an absorption phase.


RESULTS
AUC for blood pressure, heart rate and forearm vascular resistance did not change after DHE. Brachial artery diameter and compliance decreased (P < 0.01); DeltaAUC (95% confidence interval) equalled -8.81 mm h (-12.97/-4.65) and -0.98 mm2 kPa(-1) h (-1.61/-0.34), respectively. Diameter decreased (P < 0.05) from 1 until 24 h after DHE (peak decrease 9.7% at 10 h); compliance from 2 until 32 h (24.8% at 2 h). Time to reach maximum plasma concentration of DHE averaged 0.33 +/- 0.08 h (+/- s.e.mean); terminal half-life was 5.63 +/- 1.15 h.


CONCLUSIONS
DHE decreased diameter and compliance of the brachial artery whereas forearm vascular resistance remained unchanged. Thus, DHE acts on conduit arteries without affecting resistance arteries. Furthermore, a discrepancy was demonstrated between the plasma concentrations of DHE which rapidly reach peak levels and quickly decline, and its long lasting vasoconstrictor activity.
de Hoon
J N
JN
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. Jan.deHoon@uz.kuleuven.ac.be
Poppe
K A
KA
Thijssen
H H
HH
Struijker-Boudier
H A
HA
Van Bortel
L M
LM
D000328:Adult; D019540:Area Under Curve; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D004087:Dihydroergotamine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D014662:Vasoconstrictor Agents / Q000493:pharmacokinetics* / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D004087:Dihydroergotamine