Dihydroergotamine: discrepancy between arterial, arteriolar and pharmacokinetic data

Abstract

Aims: 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.

Figure 1

a) The plasma-concentration-time curve of dihydroergotamine (DHE) after a single subcutaneous administration of 0.5 mg (○, dashed line). Time course of brachial artery diameter (b) and isobaric compliance (c) after placebo (□, dashed line) and DHE (▪, solid line). d) Time course of total forearm vascular resistance after placebo (□, dashed line) and DHE (▪, solid line). Data are presented as mean±s.e. mean (n = 10). *Time points with P < 0.05 for difference between DHE and placebo; NS: no statistically significant difference.