Pharmacokinetic investigation of oral and i.v. dihydroergotamine in healthy subjects.
A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized cross-over trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz = 33 l/kg) and a high plasma clearance (CLP = 2 l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8'-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.
Wyss
P A
PA
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Rosenthaler
J
J
Nüesch
E
E
Aellig
W H
WH
D000284:Administration, Oral; D000328:Adult; D004087:Dihydroergotamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding / Q000187:drug effects; D011863:Radioimmunoassay; D014018:Tissue Distribution
D004087:Dihydroergotamine