Pharmacodynamics and Pharmacokinetics of Metocurine in Humans: Comparison to d-Tubocurarine

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Abstract
The relation of serum concentrations of metocurine and d-tubocurarine to neuromuscular blockade and the distribution and urinary excretion of metocurine were determined in humans, using radioimmunoassay for measurement of drug concentrations. Metocurine was administered at 2 dose levels (0.15 or 0.3 mg/kg) to a total of 14 neurosurgical patients. Serum concentrations of metocurine were correlated with the response of the adductor muscle of the thumb to supramaximal stimulation of the ulnar nerve as measured simultaneously by twitch tension and evoked compound electromyelography (ECEMG). A similar study was performed in another 8 neurosurgical patients, using 0.3 mg/kg d-tubocurarine (dTc), and using only the ECEMG to monitor neuromuscular transmission. The log plasma concentration-response relationship for all groups produced a sigmoid curve that was linear in the range of 20-80% paralysis. When the metocurine serum concentrations were compared at any 1 response level, there were no significant differences between the 2 dosage groups or the 2 methods employed to measure neuromuscular transmission. The mean serum metocurine concentrations (mean .+-. SE) for the pooled data from all 4 groups at 5, 25, 50, 75 and 95% of paralysis were 0.15 .+-. 0.03, 0.23 .+-. 0.04, 0.30 .+-. 0.05, 0.39 .+-. 0.06 and 0.63 .+-. 0.09 .mu.g/ml. The serum dTc concentrations (mean .+-. SE) at similar percent of paralysis were 0.34 .+-. 0.05, 0.50 .+-. 0.06, 0.62 .+-. 0.07, 0.78 .+-. 0.08 and 1.15 .+-. 0.1 .mu.g/ml. The potency ratio of metocurine to dTc based on serum concentration was .apprx. 1:2. If equipotent doses of metocurine (0.15 mg/kg) and dTc (0.3 mg/kg) were given, there was no significant difference in the time required for 50% recovery of ECEMG (53 vs. 57 min). Mean cumulative urinary excretion of metocurine at 24 h was 42 .+-. 5%. Small quantities of metocurine (5% total dose) were detected in the urine of all patients from 24-96 h after injection of the drug. Metocurine apparently is stored in body tissues and is released slowly over a period of days. Analysis of the average serum concentration-time course for metocurine and dTc, using data from a previous study for dTc, gave a triexponential equation for each drug. Significant differences between the pharmacokinetic parameters for the 2 drugs were terminal phase half-life (metocurine, 345 vs. dTc 190 min), plasma clearance (metocurine, 1.07 vs. dTc 1.86 ml/kg per min), volume of distribution, area (metocurine, 0.513 vs. dTc, 0.470 l/kg), elimination rate constant (metocurine, 0.025 vs. dTc, 0.046/min) and the entrance and exit rate constants to the shallow peripheral compartment were larger for dTc. These differences may reflect the decreased free tissue fraction of metocurine and a greater fraction of the drug bound to body tissues when compared to dTc.