Pharmacokinetics of d-tubocurarine in man: effect of an osmotic diuretic on urinary excretion.

The pharmacokinetics of d-tubocurarine (dTc) and the urinary excretion of dTc were studied in 18 neurosurgical patients with normal renal function, over a period of 96 hours. The effects of an osmotic diuretic (mannitol) on urinary elimination of dTc were determined. Following a single intravenous dose of d-tubocurarine (dTc, 0.3 mg/kg), serum levels and urinary excretion of the drug were measured. A specific radioimmunoassay was used for the analysis of dTc. Nine of the patients also received mannitol, 1 g/kg, after the injection of dTc for surgical indications. The study showed that only 45 per cent of the injected dose of dTc was excreted in 24 hours. Between 24 and 96 hours, an additional 7 per cent of the drug was excreted in the urine. The administration of mannitol, an osmotic diuretic, did not increase the excretion of dTc. The time-concentration relationship of serum concentration of dTc was analyzed. Using the four-exponential equation (data to 96 hours), the calculated volume of distribution (Vdarea) was 3.4 1/kg. This volume, which is greater than the volume of total body water, suggests that dTc is stored in certain tissues in the body and slowly released over a period of days to weeks.

Comparative pharmacokinetics of d-tubocurarine and metocurine in man.

To compare the pharmacokinetics of d-tubocurarine and metocurine in man, concentrations of 3H-d-tubocurarine and 14C-metocurine (0,0,N-trimethyl-tubocurarine) in plasma, urine and bile were determined after intravenous administration of d-tubocurarine, 0.15 mg/kg (five patients), and metocurine, 0.05 mg/kg (five patients), in patients anesthetized with thiopental and nitrous oxide for cholecystectomy. Plasma disappearances of both drugs were triexponential, with mean terminal half-lives of 346 and 217 min for d-tubocurarine and metocurine, respectively. By ion-pair thin-layer chromatography, no metabolite of either compound was found in urine or bile. Renal excretions 48 hours after injection ranged from 46 to 95 per cent of the dose for d-tubocurarine and from 46 to 58 per cent for metocurine. Mean total-body clearances were 56 and 96 ml/min for d-tubocurarine and metocurine, respectively. Biliary elimination of d-tubocurarine was greater than that of metocurine: within 48 hours 11.8 and 2.1 per cent of the doses were excreted in bile, respectively. The observed differences in total-body clearances and volumes of distribution (V1) may be partly explained by greater protein binding of d-tubocurarine. The results indicate that biliary excretion is an alternative route of elimination for d-tubocurarine only. Also, d-tubocurarine is less dependent on renal excretion for its elimination, and probably is preferable to metocurine for use in patients with renal failure.

Kinetics of intercompartmental disposition and excretion of tubocurarine, gallamine, alcuronium and pancuronium in patients with normal and impaired renal function.

Pharmacokinetic data of tubocurarine, gallamine, alcuronium and pancuronium in patients with normal and without renal function are taken from the literature. They are adapted to an open three compartment pharmacokinetic model, and the proportional intercompartmental distribution is calculated as a function of time from 1 min to 8 h. All drugs show similar kinetic properties: During the first 10 min rapid disappearance from compartment 1 results in saturation of compartment 2. Maximum saturation of compartment 3 is achieved after 1 to 2 h followed by a gradual disappearance of the relaxants from the whole system. 20-25% of the dose undergo sequestration apart from intercompartment equilibrium. In normal individuals sequestration is observed after 2 to 3 h whereas in anuric patients it is already demonstrated during the first hour. Intercompartmental redistribution is the basic principle governing the pharmacodynamic profile of all of the four drugs if given in clinical dosage.

Biliary excretion of some diquaternary ammonium cations in the rat, guinea pig and rabbit.

1. The extent of the excretion in the bile and urine of the (14)C-labelled dications, diquat, paraquat, morfamquat, decamethonium and dimethyltubocurarine in bile-duct-cannulated rats, guinea pigs and rabbits was examined. 2. These compounds were excreted unchanged in bile and urine, except diquat, which was metabolized to a significant extent (18% of the dose) in the rabbit only. 3. The extent of the biliary excretion of diquat (mol wt. of ion 184), paraquat (186), decamethonium (258) and morfamquat (469) was less than 10% of the dose in the three species, whereas that of dimethlytubocurarine (653) was greater than 10% in the rat and rabbit but not in the guinea pig. 4. These results together with data from the literature suggest that the molecular weight at which the excretion of dications in the bile exceeds 10% of the dose is in the region of 500-600, which differs from the values for monocations (Hughes et al., 1973) and anions (Millburn et al., 1967; Hirom et al., 1972).