The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).

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ABSTRACT:Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of central nervous system drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO 2 euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, or cervical dislocation). Further investigations demonstrated that CO 2 euthanasia led to a reduction in blood pH in both rats and mice, which was not observed with the other sampling methods. The use of CO 2 euthanasia resulted in a decrease in the brain/plasma ratio of Org B, largely as a result of increased plasma concentrations. The pharmacokinetics of a basic drug, raloxifene, in rat were also influenced by sampling technique. CO 2 euthanasia before sampling, resulted in a 2-to 3-fold increase in the area under the drug concentration-time curve, a decrease in plasma clearance, and a decrease in the steady-state volume of distribution compared with isoflurane anesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO 2 exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

SummaryThe effect of charcoal haemoperfusion on the pharmacokinetics of diltiazem is described in a patient with severe clinical toxicity following acute overdose. The patient presented within 3 h following acute ingestion of multiple medications including sustained-release diltiazem. Routine resuscitation and supportive care were administered, but hypotension did not resolve despite intravenous fluids and infusions of calcium, adrenaline, noradrenaline and vasopressin. Multipledoses of activated charcoal, haemodialysis and charcoal haemoperfusion were prescribed to expedite the elimination of diltiazem. The maximum diltiazem concentration (577 lg.l )1 ) was recorded 7 h post ingestion which was followed by an erratic and prolonged elimination phase.The maximum clearance of diltiazem due to haemoperfusion was calculated to be 19.4 and 15.1 ml.min )1 at different times, equating to removal of approximately 1.5 mg diltiazem during 4 h of haemoperfusion. Haemoperfusion did not appear to remove sufficient diltiazem to recommend its routine use in the treatment of patients with acute diltiazem overdose. Severe cardiovascular depression and death is reported from self-poisoning with diltiazem. In overdose these effects manifest as bradycardia and hypotension which relates more to decreased systemic vascular resistance than cardiac contractility [1]. Standard and sustained-release formulations of diltiazem differ in their pharmacokinetic profile. Acute poisoning with the standard formulation usually leads to a rapid onset of toxicity which largely resolves within 12 h. This differs from the more frequently used sustainedrelease formulation where toxicity is delayed in onset and prolonged [1,2]. For example, in two recent cases only mild hypotension preceded the development of a cardiac arrest more than 13 and 18 h post ingestion [3,4]. The variable time-course of toxicity relates to unpredictable changes in the concentration of diltiazem. This may reflect erratic absorption from an aggregate of sustainedrelease tablets [2], or dose-related factors such as ileus [5][6][7] or changes in clearance due to enzyme saturation or hepatic hypoperfusion with marked hypotension [1,8].The initial management of acute diltiazem poisoning includes gastrointestinal decontamination and the administration of intravenous fluids and calcium. Unfortunately, many cases are refractory to these first-line treatments, requiring other interventions, including atropine, glucagon, vasopressors, temporary pacing, balloon pump,

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