Modified carbon paste sensor for the potentiometric determination of neostigmine bromide in pharmaceutical formulations, human plasma and urine.

A novel, simple, rapid, selective and sensitive method for the determination of neostigmine (Ns) ion in its bulk powder, different pharmaceutical dosage forms, and biological fluids (plasma and urine) using four modified carbon paste electrodes was developed. Sensor 1 is based on ion-association Ns-TPB, sensor 2 used Ns-PT, sensor 3 comprises a mixture of (Ns-PT+Ns-TPB) and sensor 4 was constructed using (Ns-PT+ß-CD). Solvent mediator 2-NPPE exhibited a proper behavior including Nernstian slope ranging from 61.5±0.5 to 64.5±0.5 mV per decade over the pH range of 3.8-10 for the four sensors. Linear responses of Ns within the concentration range 1.0×10(-7)-1.0×10(-2) mol/L were obtained. The response time is very short (≤10s) with a detection limit 6.3×10(-8) M. In flow injection analysis (FIA), sensor 3 shows a Nernstian slope value 75.5±0.5 mV per decade within the concentration range of 1×10(-6)-1×10(-2) mol/L and with a detection limit 7.5×10(-7) mol/L. The utility of mixed or additives of ß-CD had a significant influence on increasing the sensitivity of sensors 3 and 4 compared to sensors 1 and 2. The sensors were applied for the determination of neostigmine (Ns) ion in its bulk powder, different pharmaceutical dosage forms, and biological fluids (plasma and urine). The results obtained were satisfactory with excellent percentage recovery comparable with official method for the assay based on non-aqueous titration using perchloric acid as a titrant.

Reversed-phase, ion-pair liquid chromatography of quaternary ammonium compounds: determination of pyridostigmine, neostigmine and edrophionium in biological fluids.

A reversed-phase, ion-pair liquid chromatographic method for the quantitative determination of quaternary acetylcholinesterase inhibitors is described. The method uses an ion-pair extraction to isolate the drugs from biological material prior to liquid chromatographic separation and online UV detection at 214 nm. Quantiation down to 5 ng/ml and within-day precison with coefficient of variation (C.V.) of 1.5% (n = 10, x = 100 ng/ml) for neostigmine, C.V., 1.7% (n = 10, x = 80 ng/ml) for pyridostigmine and C.V., 1.5% (n = 10, x = 100 ng/ml) for edrophonium have been achieved. The assay was designed for pharmacokinetic studies of these drugs in anesthetized patients.

Kinetics and metabolism of intramuscular neostigmine in myasthenia gravis.

Neostigmine kinetics and metabolism were studied after intracellular administration to 8 patients with myasthenia gravis. The plasma neostigmine level declined monoexponentially from 21 +/- 2 to 9 +/- 1 ng/ml between 30 and 120 min. The data were interpreted in terms of a 1-compartment model. Estimates of plasma half-life (t1/2) ranged from 51.1 to 90.5 min; apparent volume of distribution varied from 32.0 to 60.6 1; and total body clearance from 434 to 549 ml/min. Approximately 80% of the drug was eliminated in urine within 24 hr either as unchanged neostigmine or its metabolites. Approximately 50% of the dose was eliminated as the unchanged drug, 15% as 3-hydroxyphenyltrimethylammonium, and 15% as other unidentified metabolites. The neostigmine t1/2, based on the urinary excretion of the unchanged drug, ranged from 90.2 to 118.7 min. It was concluded that neostigmine was eliminated by renal and extrarenal mechanisms.

Metabolism and exretion of 3-hydroxyphenyltrimethylammonium and neostigmine.

1. Carbon-14 labelled 3-hydroxyphenyltrimethylammonium (3-OH PTMA), an active metabolite of neostigmine, has been given to rats by intramuscular injection and its excretion, distribution and metabolism have been studied.2. A method is described for the separation and estimation of free and conjugated 3-OH PTMA in urine and liver.3. In the first hour, about 20% of a dose is excreted in the urine as free 3-OH PTMA and thereafter the rate of excretion of glucuronide conjugate exceeds that of free 3-OH PTMA. In 24 hr 76.8% of the dose is excreted in urine mainly as the conjugate.4. The peak concentration of radioactivity in blood occurs within 30 min and in liver within 1 hr after administration. More than 90% of the radioactivity in liver occurs as the glucuronide conjugate. Relatively high concentrations of radioactivity were found in liver and heart.5. In the hen 3-OH PTMA is rapidly excreted by renal tubular secretion.6. Experiments with carbon-14 labelled neostigmine show that up to 1 hr mainly unchanged neostigmine is excreted in urine; thereafter increasing amounts of free 3-OH PTMA and its glucuronide conjugate are excreted.7. It is concluded that the duration of action of neostigmine is determined by its rapid renal excretion and by its metabolism to the glucuronide conjugate of 3-OH PTMA.