Flow injection potentiometric determination of pancuronium bromide in pharmaceutical preparation and urine samples using modified carbon paste electrodes.

Carbon paste electrodes for pancuronium bromide was prepared based on ion association complexes of pancuronium bromide with sodium tetraphenylborate (NaTPB) or ammonium reineckate using dibutyl phthalate as solvent mediator and tetradodecylammonium tetrakis-(4-chlorophenyl)borate (ETH 500) as lipophilic additive. The sensors showed a near-Nernstian slope of 28.1 mV concentration decade(-1) at 25°C within the concentration range 6.31×10(-6)-1.00×10(-2) M in case of pancuronium-tetraphenylborate electrode and 26.6 mV concentration decade(-1) in the concentration range 5.66×10(-5)-1.00×10(-2) M in case of pancuronium-reineckate electrode. The sensors were successfully applied for the potentiometric determination of pancuronium bromide in pharmaceutical preparation and biological fluids in batch and flow injection conditions.

Cholinesterase inhibition based determination of pancuronium bromide in biological samples.

Pancuronium bromide (PCBr) inhibition effect on enzyme cholinesterase from pooled human serum (Che, EC 3.1.1.8 acylcholine acylhydrolase) was used for development of a spectrophotometric kinetic method for PCBr determination in human serum and urine. Optimal conditions for the basic and inhibitor reactions were established: pH=7.7 and substrate concentration c(benzoylcholine chloride)=1.33 mmol/L. Kinetic parameters were also determined: Michaelis-Menten's constant K(M)=0.40 mmol/L, maximal reaction rate V(max)=52.2 micromol/L min, inhibition constant K(i)=0,56 micromol/L and IC(50)=1.31 micromol/L. Linear dependence between the reaction rate and inhibitor concentration exists in PCBr concentration range 8.20-68.25 nmol/L, which corresponds to the real sample concentrations from 0.328 to 2.730 micromol/L. The method detection and quantification limits were 2.01 nmol/L and 6.67 nmol/L, respectively. Precision of the method was tested for three pancuronium concentrations (10.70, 29.35 and 51.25 nmol/L). Relative standard deviation (RSD) was in the range 0.15-7.45%. Accuracy was examined by standard addition method. Influence of the substances usually present in serum and urine on the reaction rate was tested. The developed method was applied for PCBr content determination in serum model samples, urine model samples and in urine taken during surgery. The method has good sensitivity, accuracy, precision and it is suitable for clinical practice.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Attempted murder with pancuronium.

A nurse was accused of attempting to murder her anesthesiologist husband on two occasions by administering to him a neuromuscular blocking agent. In both episodes, urine specimens were obtained from the victim shortly after the suspected assaults. The samples were initially tested fluorometrically using Rose Bengal dye as a pairing agent. Both were presumptively positive for pancuronium. Confirmation of these results was achieved by pairing the drug with potassium iodide, extracting the complex, and submitting the extract to thin-layer chromatography (TLC) cleanup, elution at the appropriate retardation factor (Rf), and, finally, gas chromatography/mass spectrometry (GC/MS) analysis in the selected-ion monitoring mode. The two quaternary amines of pancuronium appear to undergo pyrolytic N-demethylation in the injection port to yield an entity amenable to capillary column gas chromatography. The mass spectrum of the compound consists of a base peak of m/z 322, with additional fragments of 292, 323, 338, and 397 m/z, each of which was monitored. The confirmed positive findings were instrumental in adjudicating the case.

Mass spectrometric assay for determination of pancuronium and vecuronium in biological fluids utilizing the moving belt introduction system.

An assay for the determination of the neuromuscular blocking agents pancuronium bromide and vecuronium bromide in plasma or urine has been developed. This method is based on syringe application of sample extracts to the moving belt surface and single metastable transition monitoring of the elimination of acetic acid from the ion of m/z 543 during chemical ionization. The analysis shows good linearity over three orders of magnitude and is capable of analyzing for the compounds below the 5 ng ml-1 level. The assay has been used in preliminary pharmacokinetic studies of the biological fluids of surgical patients. The utility of the method for simultaneous determination of the deacetylated metabolites of these two drugs has also been investigated.

Quantitation of pancuronium, 3-desacetylpancuronium, vecuronium, 3-desacetylvecuronium, pipecuronium and 3-desacetylpipecuronium in biological fluids by capillary gas chromatography using nitrogen-sensitive detection.

A sensitive and specific capillary gas chromatographic (GC) assay was developed for the quantitation of the quaternary ammonium steroidal neuromuscular blocking drugs pancuronium (PANC), vecuronium (VEC) and pipecuronium (PIP), as well as the metabolites 3-desacetylpancuronium (3-desPANC) and 3-desacetylvecuronium (3-des VEC) in plasma, bile and urine; the putative metabolite 3-desacetylpipecuronium (3-des PIP) was extracted and quantitated only in urine. The procedure employed a single dichloromethane extraction of the iodide ion-pairs of the monoquaternary or bisquaternary ammonium compounds (including internal and external standards) from acidified, ether-washed biological fluid followed by the formation of stable O-tert.-butyldimethylsilyl derivatives at the 3-hydroxy steroidal position of the metabolites. An automated capillary GC system fitted with a nitrogen-sensitive detector and an integrator was then used to analyze and quantitate both parent compounds and their derivatized metabolites. Optimal extraction, derivatization and GC conditions, as well as short-term stability and recoveries of these drugs and metabolites in plasma, are reported. Electron ionization mass spectrometry combined with GC was used to confirm the identities of compounds eluted from the column. The assay demonstrated a 10(3)-fold linear range up to 5000 ng/ml for PANC, VEC, 3-des VEC and PIP, and lower limits of detection with adequate precision of 2 ng/ml for PANC, VEC and PIP, and 4 ng/ml for 3-des VEC; 3-des PANC was linear from 8 to 500 ng/ml while 3-des PIP was linear from 25 to 1000 ng/ml. The precision (coefficient of variation) of the calibration curves for underivatized drugs and their derivatized metabolites over the linear ranges was 2-20% and the reproducibility of the assay over a range of clinical concentrations of these drugs found in human plasma was 5-16% for PANC, 2-4% for VEC and 6-11% for PIP. No interferences were detected in the assay of plasma samples from 106 surgical patients.

Disposition of vecuronium bromide in the cat.

The disposition of vecuronium bromide has been investigated in six normal cats (group I) and in six cats with ligated renal pedicles (group II). A combined fluorimetric and chromatographic technique was used to determine the concentrations of vecuronium and its metabolites in biological material. After i.v. injection of 0.6 mg kg-1, vecuronium disappeared rapidly from the plasma of the normal cat. Concentrations decreased bi-exponentially with half-lives of 4.6 and 31 min, respectively. The steady state volume of distribution was 0.23 litre kg-1 and the clearance 11 ml min-1 kg-1. Seventy percent of an i.v. dose of vecuronium (or its metabolites) was recovered: 15% in the urine, 40% in the bile and 15% in the liver. Only 3.8% of this consisted of the 3-hydroxy metabolite. There were no significant differences in pharmacokinetic data or in the amounts of vecuronium and its metabolites recovered in cats with ligated renal pedicles. The 15% of vecuronium normally excreted by the kidney was compensated for by increased hepatic and biliary concentration of vecuronium.

Variations in pancuronium requirement, plasma concentration, and urinary excretion induced by cardiopulmonary bypass with hypothermia.

To determine the effects of cardiopulmonary bypass (CPB) and hypothermia on the neuromuscular blockade produced by pancuronium, this relaxant was infused intravenously into 10 anesthetized patients to produce and maintain 90% depression of the twitch tension of the adductor pollicis muscle following supramaximal ulnar nerve stimulation. Infusion rates, plasma concentration of pancuronium, and adductor pollicis temperature were measured every 15 min. During the normothermic period preceding the start of CPB, the pancuronium requirement, the pancuronium plasma concentration, and muscle temperature were mean (mean +/- SEM): 238 +/- 12 micrograms . m-2 . 15 min-1, 0.31 +/- 0.01 microgram/ml, and 33.9 +/- 0.1 degrees C, respectively. At the beginning of CPB, the pancuronium infusion rate increased to 362 +/- 32 micrograms . m-2 . 15 min-1 (P less than 0.001) despite a decrease in the muscle temperature to 29.2 +/- 0.9 degrees C (P less than 0.001) and in pancuronium plasma concentration to 0.22 +/- 0.02 microgram/ml. During sustained muscle hypothermia to 28.3 +/- 0.4 degrees C the pancuronium plasma concentration remained constant at 0.22 +/- 0.01 micrograms/ml (P less than 0.001) while the requirement decreased to 94 +/- 15 micrograms . m-2 . 15 min-1 (P less than 0.001). After the muscle temperature was returned to 34 +/- 0.6 degrees C, the plasma pancuronium concentration and requirements increased to 0.35 +/- 0.05 microgram/ml and 392 +/- 32 micrograms . m-2 . 15 min-1 (P less than 0.001), respectively. After CPB, these values were 0.39 +/- 0.04 microgram/ml and 239 +/- 25 microgram . m-2 . 15 min-1. These results demonstrate that pancuronium requirements are increased at the beginning of CPB because of circulatory volume changes and again during rewarming of the patient once muscle temperature reaches about 34 degrees C.

Pharmacokinetics of pancuronium in man: a linear system.

Pancuronium in bolus doses of 40 to 350 microgram/kg was administered to surgical patients in order to evaluate the linearity of its pharmacokinetics. The profile of the plasma decay curve and of its urinary elimination were compared with reference to the administered dose. It was possible to superimpose the dose-normalized plasma decay-curves. The parameters of the two compartment-open model used to describe the pharmacokinetics of pancuronium were not influenced by the dose. The elimination half-life was 89 +/- 20 min and the plasma clearance was 1.84 +/- 0.38 ml/min/kg. The profiles of cumulative urinary excretion were also dose-independent. After 6 and 24 h, 57% and 69% of the administered dose, respectively, had been excreted in the urine. The results indicate that the pharmacokinetics of pancuronium is linear.

A suicide by pancuronium bromide injection: evaluation of the fluorometric determination of pancuronium in postmortem blood, serum and urine.

A fatal case of suicidal injection of pancuronium bromide is presented. Pancuronium was detected in blood and urine by ion-pair extraction and fluorometry. An evaluation of the fluorometric procedure for the determination of pancuronium in postmortem blood, serum and urine is presented. Stability of the extracted ion-pair, possible interferences from other drugs, and the effects of specimen storage were studied.

Pancuronium blood level monitoring in patients with tetanus.

Overdosage of muscle relaxant has been given as a possible explanation for the hypotensive episodes occurring during the management of tetanus. The aim of the present work was to study the pharmacokinetics of pancuronium during long term infusion. Pancuronium was administered to eight patients with severe tetanus for a period varying from 8 to 24 days. The concentration of pancuronium was measured daily in plasma and urine using a fluorimetric method. The plasma concentration varied from 0.27 to 0.48 microgram/ml. No tendency to accumulation was observed. The plasma concentration fell rapidly below the level associated with muscle relaxation when pancuronium was discontinued. This absence of accumulation can be explained by a rapid elimination of pancuronium through the kidney according to a process of ultrafiltration.

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.

Disposition kinetics of pancuronium bromide in patients with total biliary obstruction.

Plasma concentrations of pancuronium were measured in nine patients undergoing surgery because of total biliary obstruction. When compared with the averaged model-independent pharmacokinetic parameters obtained for normal patients, the terminal half-life of 270 min was more than twice normal (132 min, P less than 0.001); the plasma clearance of 59 ml min-1 was less than half the normal rate for pancuronium (123 ml min-1, P less than 0.003). These significant alterations to the pharmacokinetics of pancuronium were associated with prolongation of neuromuscular blockade. Following a bolus injection of pancuronium 6 mg, there was a mean time of 114 min (normals 70 min, P less than 0.05) before the evoked twitch response had returned to 5% of the control value. The pattern of urinary excretion of the drug and its metabolites did not differ from that of normal patients. To avoid excessive dosage during prolonged surgery for total biliary obstruction, it is recommended that supramaximal nerve stimulation be used to indicate the need for the administration of further doses of pancuronium.

[The metabolism of pancuronium in man]. / Der Stoffwechsel von Pancuronium beim Menschen

The metabolic disposition of pancuronium was investigated in man under clinical condition. Pancuronium and its desacetylated derivatives were determined in body fluids using the previously described bromophenol blue method (3). The metabolites were isolated by thin layer chromatography. One minute after the intravenous injection of a mg of pancuronium the drug reaches a serum concentration of 2,2 plus or minus 0,2mug/ml. As an exponential function the concentration curve then falls to half of the initial value during the first 30 to 60 min. The end of the neuromuscular block conincides with a concentration of 0,1 to 0,3 mug/ml serum which is reached about 2 hours after the injection. After 3 to 4 hours no more pancuronium can be detected in the serum. The renal elimination of pancuronium can be folowed up for 12 hours. On average half of the injected dose is recovered in the urine. 80% of this proportion is unchanged pancuronium and 20% desacetylated metabolites. The monodesacetylated derivatives of pancuronium are still pharmacologically active. The biliary excretion 24 hours after the administration of pancuronium accounts for 5 to 10% of the injected dose...