Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat
Bredberg, U.; Paalzow, L.
Drug Metabolism and Disposition the Biological Fate of Chemicals 18(3): 338-343
1990
ISSN/ISBN: 0090-9556 PMID: 1974196 Document Number: 367017
The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Spraque-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 .mu.mol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 .mu.mol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at a steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively. The disposition of MEM following MS administration displayed an erratic profile, especially at low plasma concentrations. When MEM was administered iv, a second peak or plateau in the plasma concentration-time profile appeared 2-4 hr after administration. Both these latter findings indicate enterohepatic recirculation of MEM.