Pharmacology of Laudanosine in Dogs

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Abstract
The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg .cntdot. kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 .+-. 24 min (mean .+-. SD) and a clearance of 25 .+-. 8 ml .cntdot. kg-1 .cntdot. min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng .cntdot. ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (< 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg .cntdot. kg-1 iv every 5 min. With cumulative doses of 2-8 mg .cntdot. kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg .cntdot. kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg .cntdot. kg-1 iv) and returned to control levels 4 min later. The authors conclude that laudanosine in dogs readily crosses the blood-brain barrier and can produce hypotension, signs of "awakening" from halothane anesthesia, and seizures. In addition, laudanosine is excreted unchanged by the kidney, and its metabolites are excreted by both the kidney and liver.