LC/MS/MS analysis of quaternary ammonium drugs and herbicides in whole blood.

Quaternary ammonium drugs (atracurium, bretylium, edrophonium, ipratropium, mivacurium, neostigmine, pancuronium and rocuronium) and herbicides (difenzoquat, diquat and paraquat) in human whole blood were analysed by LC/MS/MS with positive electrospray ionisation (ESI), following extraction with Bond Elut LRC-CBA cartridges. Internal standards were benzyldimethylphenylammonium chloride monohydrate and ethyl viologen for drug and herbicide analysis, respectively. Ion-pair chromatography used heptafluorobutyric acid (15 mM)-ammonium formate (20 mM) buffer adjusted to pH 3.30 with formic acid and a linear gradient from 5 to 90% methanol run over 18 min. Recoveries ranged from 79.7 to 105.1%, detection limits were between 3.6 and 20.4 ng/ml and the intra- and inter-day precisions were less than 18.6% at a concentration of 10 ng/ml. The method was applied to a case of accidental paraquat poisoning in which the concentration of paraquat in blood was 0.64 mg/l, which is within the range associated with fatal paraquat poisoning.

Pharmacokinetics and pharmacodynamics of edrophonium in elderly surgical patients.

The effect of age (over 70 yr) on the pharmacokinetics and pharmacodynamics of edrophonium was evaluated in seven patients aged 76-87 yr and in seven patients aged 27-57 yr. When elderly patients were compared with younger controls, the elderly exhibited a statistically significant decreased plasma clearance (5.9 +/- 2 versus 12.1 +/- 4 mL.kg-1.min-1) and a prolonged elimination half-life (84.2 +/- 17 versus 56.6 +/- 16 min). Pharmacodynamically, a higher concentration of edrophonium is required in elderly patients to produce the same effect as in the younger controls. This observation may be explained in part by changes in neuromuscular transmission that are a function of the aging process. In addition, even though plasma concentrations were significantly greater at every sampling point in the elderly than the younger group, there was no difference between either the maximum duration or the total duration of action of edrophonium in the two groups. The maximum duration of action of edrophonium in both groups was very brief (1.3-2.2 min). These results contrast with a previous study of the anticholinesterases neostigmine and pyridostigmine, in which the action of these drugs was significantly prolonged in elderly patients. Explanations for the observed differences between edrophonium and other anticholinesterases may relate to differences in chemical structure and the possibility that edrophonium produces antagonism of neuromuscular blockade by a different mechanism than neostigmine or pyridostigmine.

Pharmacokinetics of edrophonium in anephric and renal transplant patients.

The pharmacokinetics of edrophonium were determined in patients anaesthetized with nitrous oxide and halothane undergoing kidney transplant nephrectomy (n=6) or transplantation of a live related donor kidney (n = 6). Serum concentrations of edrophonium were assayed by high pressure liquid chromatography and pharmacokinetic variables computed using non-compartmental analysis. Patients undergoing transplant nephrectomy had a significant increase in elimination half-life and a significant decrease (67%) in serum clearance when compared with kidney transplant recipients or patients with normal renal function. Pharmacokinetic indices for edrophonium in patients receiving a kidney transplant did not differ from those in patients with normal renal function. We conclude that absence of renal function decrease excretion of edrophonium to an extent similar to that of other acetylcholinesterase inhibitors, neostigmine and pyridostigmine.

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.

Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man: a reappraisal.

The ability of edrophonium to reverse the nondepolarizing neuromuscular blockade produced by pancuronium was studied in 40 adult patients during light nitrous oxide--enflurane anesthesia. Antagonism of paralysis was attempted when the train-of-four fade ratio had spontaneous recovered in various extents. Edrophonium was administered in incremental doses intravenously either until the fade ratio increased to 0.70 or more or until the total dose of drug amounted to 0.5 mg/kg. All patients who had spontaneous recovery of train-of-four fade ratios to at least 0.10 had adequate reversal with edrophonium. When the train-of-four count was three or fewer visible twitches, the response to endrophonium was unpredictable. No evidence of recurarization was seen.

Plasma concentration of edrophonium in man.

The plasma concentration of edrophonium was measured in man after intravenous administration. In 5 patients, the clearance of edrophonium from the circulation during the 1-hr period of sampling was invariably resolved into 2 exponential components. An initial rapid phase of elimination from plasma (T/2 = 0.54 TO 1.92 Min) was followed by a much slower decline (T/2 = 24.23 to 45.00 Min), corresponding to the fall in concentration between 10 and 60 min. In parallel experiments in the rat, the clearance of 14C-edrophonium was resolved into 3 exponential components, although the final component could not be reliably defined until 1 to 3 hr after intravenous injection. It is suggested that the rapid fall in the plasma concentration of edrophonium in both species is not dependent on metabolism or excretion, but is due to the rapid uptake of the drug by the liver and kidneys.

The effect of edrophonium on erythrocyte acetylcholinesterase and neuromuscular function in the rat.

1. The relation between the concentration of edrophonium in plasma, inhibition of red cell acetylcholinesterase, and neuromuscular transmission was studied in the rat. 2. In both in vivo and in vitro conditions, red cell acetylcholinesterase activity was predictably related to the concentration of the quaternary amine. 3. After low doses of edrophonium (1.0 mumol/kg) there was a significant correlation between the monophasic potentiation of twitch tension and the plasma concentration of the drug. In contrast, with higher doses of edrophonium (4.0 or 10.0 mumol/kg) a biphasic potentiation of twitch tension was observed; this was only correlated with the plasma concentration of the drug during the secondary decline in neuromuscular facilitation. Subsequent recovery of normal neuromuscular transmission invariably occurred at a constant plasma concentration of edrophonium.

The pharmacokinetics of (14C)-edrophonium in normal wistar rats and homozygous Gunn rats with ligated renal pedicles.

1 The distribution kinetics of [(14)C]-edrophonium were studied in both normal Wistar and homozygous Gunn rats with ligated renal pedicles.2 After intravenous injection the plasma concentration-time curve of [(14)C]-edrophonium was adequately fitted by a triexponential function in both species of rat and interpreted in terms of a three compartment model.3 The influence of the route of administration (i.e., systemic venous versus hepatic portal) of [(14)C]-edrophonium on its concentration in plasma was studied in normal Wistar rats with ligated renal pedicles. There was a marked difference in the area under the plasma concentration-time curve depending on the route of administration.4 The parameters of the model were determined and compared.5 The value of the metabolism rate constant was approximately the same in both species of rat. This suggests that the rate of conjugation of [(14)C]-edrophonium is unaltered in the homozygous Gunn rat despite the genetic lesion in UDP-glucuronyltransferase.

The removal of 14 C-edrophonium from the circulation.

The clearance of (14)C-edrophonium from plasma was studied in the rat. Distribution studies showed that 5 min after intravenous injection of the drug, more than half the dose was present in the liver and the kidneys. The concentration in these organs was approximately 20 times the level in other tissues. The plasma concentration of (14)C-edrophonium was invariably expressed as the sum of two exponential terms, suggesting that the drug may return to the circulation from other tissues as the plasma level falls.