Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat
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1Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala, Sweden.
Abstract:
The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/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 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
This study investigated the pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) in rats. MS exhibited high plasma clearance, while MEM showed lower clearance and saturable formation from MS.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Toxicology
Background:
- Methysergide (MS) is a medication with potential toxicities.
- Understanding its pharmacokinetic profile and that of its metabolite, methylergometrine (MEM), is crucial for safe use.
Purpose of the Study:
- To characterize the pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) in Sprague-Dawley rats.
- To evaluate the impact of different doses and infusion rates on MS and MEM disposition.
- To determine plasma protein binding and blood/plasma partitioning of MS.
Main Methods:
- Intravenous administration of MS and MEM at various doses to male Sprague-Dawley rats.
- Constant rate intravenous infusion of MS at different rates.
- Measurement of plasma and blood concentrations using High-Performance Liquid Chromatography (HPLC) with fluorescence detection.
- Determination of plasma protein binding and blood/plasma partitioning.
Main Results:
- Methysergide (MS) demonstrated high plasma clearance (74.2-102 ml/min per kg) and dose-dependent disposition.
- Methylergometrine (MEM) exhibited significantly lower plasma clearance (5-6 times less than MS) but a similar volume of distribution.
- MEM formation from MS was low and appeared to be saturable, with decreased formation clearance at higher MS infusion rates.
- MS plasma protein binding averaged 84.2% and blood/plasma partitioning was 1.67%.
Conclusions:
- Methysergide (MS) is rapidly cleared in rats, with its metabolite methylergometrine (MEM) having a slower elimination rate.
- The saturable formation of MEM suggests a potential pathway for toxicity management.
- These findings provide essential pharmacokinetic data for methysergide and its metabolite in a preclinical model.